Methods for making oxidation-resistant cross-linked polymeric materials

ABSTRACT

The present invention relates to methods for making cross-linked oxidation-resistant polymeric materials and preventing or minimizing in vivo elution of antioxidant from the antioxidant-containing polymeric materials. The invention also provides methods of doping polymeric materials with a spatial control of cross-linking and antioxidant distribution, for example, vitamin E (α-Tocopherol), and methods for extraction/elution of antioxidants, for example, vitamin E (α-tocopherol), from surface regions of antioxidant-containing polymeric materials, and materials used therewith also are provided.

This application is a continuation of U.S. application Ser. No.14/036,586 (allowed) filed Sep. 25, 2013, which is a continuation ofU.S. application Ser. No. 13/562,867 filed Jul. 31, 2012, now U.S. Pat.No. 8,569,395, which is a continuation of U.S. application Ser. No.12/522,328 filed Apr. 5, 2010, now U.S. Pat. No. 8,293,811, which is a371 of International App. No. PCT/US2008/051982 filed Jan. 25, 2008,which claims priority to Provisional App. No. 60/892,346 filed Mar. 1,2007, Provisional App. No. 60/889,037 filed Feb. 9, 2007, andProvisional App. No. 60/886,527 filed Jan. 25, 2007. The entire contentsof the above-identified applications are hereby incorporated byreference.

FIELD OF THE INVENTION

The present invention relates to methods for making oxidation-resistantcross-linked polymeric materials that contains antioxidants andpreventing or minimizing in vivo elution of antioxidant from theantioxidant-containing polymeric materials. Methods of doping polymericmaterials with a spatial control of antioxidant distribution and/or witha spatial control of cross-linking, and methods of extraction ofantioxidants from antioxidant-containing polymeric materials, andmaterials that can be used therewith also are provided.

BACKGROUND OF THE INVENTION

Polymeric material, such as ultra-high molecular weight polyethylene(UHMWPE), is used in load bearing applications. In humans, it can beused in total joint prostheses. Wear of the polyethylene components overyears is known to compromise the longevity and performance of totaljoints in the long-term. Radiation cross-linking has been shown toreduce the wear rate of polyethylene and thus extend the longevity oftotal joint reconstructions. Radiation cross-linking also generatesresidual free radicals, which are known to cause oxidation andembrittlement in the long-term. Therefore, it is crucial to eithereliminate or stabilize the free radicals so that deleterious oxidationis avoided or minimized. One method of free radical elimination throughirradiation and melting were described by Merrill et al. (see U.S. Pat.No. 5,879,400). This is an acceptable and widely used method; however,such a melt history also reduces the crystallinity of the polyethyleneand thus affects its mechanical and fatigue properties (see Oral et al.,Biomaterials, 27:917-925 (2006)).

Other methods that avoids melting after irradiation is the onedescribed, among other things, by Muratoglu and Spiegelberg (see U.S.application Ser. No. 10/757,551, filed Jan. 15, 2004; US 2004/0156879).These methods use an anti-oxidant, such as α-tocopherol, to stabilizethe free radicals in irradiated polymeric material and prevent long-termoxidation. According to certain embodiments of these methods,α-tocopherol can be incorporated into polymeric material afterirradiation through contact and diffusion.

α-Tocopherol can be used to lessen or eliminate reactivity of theresidual free radicals in irradiated UHMWPE to prevent oxidation. Theincorporation of α-tocopherol into irradiated UHMWPE can be achievedthrough either blending α-tocopherol with the UHMWPE powder prior toconsolidation or diffusing the α-tocopherol into UHMWPE afterconsolidation of powder, both of which are taught in U.S. applicationSer. No. 10/757,551. The latter also can be performed after theconsolidated UHMWPE is irradiated. Since radiation cross-links theUHMWPE and thus increases its wear resistance, it can be beneficial toirradiate the consolidated UHMWPE in its virgin state without anyα-tocopherol present. On the other hand, cross-linking has been shown todecrease certain mechanical properties and fatigue resistance of UHMWPE(see Oral et al., Mechanisms of decrease in fatigue crack propagationresistance in irradiated and melted UHMWPE, Biomaterials, 27 (2006)917-925). Wear of UHMWPE in joint arthroplasty is a surface phenomenonwhereas fatigue crack propagation resistance is largely a property ofthe bulk, other than the surface. Therefore, UHMWPE with highcross-linking on the surface and less cross-linking in the bulk can bebeneficial as an alternate bearing in joint arthroplasty. Oral et al.(Characterization of irradiated blends of α-tocopherol and UHMWPE,Biomaterials, 26 (2005) 6657-6663) have shown that when present inUHMWPE, α-tocopherol reduces the efficiency of cross-linking of thepolymer during irradiation. Spatial control of vitamin E concentrationfollowed by irradiation can spatially control cross-linking as well. Itcan be desirable to add α-tocopherol after radiation cross-linking ifhigh cross-linking is desired and that is possible by diffusingα-tocopherol into irradiated and consolidated UHMWPE. Diffusion andpenetration depth in irradiated UHMWPE has been discussed. Muratoglu etal. (see U.S. application Ser. No. 10/757,551, filed Jan. 15, 2004; US2004/0156879) described, among other things, high temperature dopingand/or annealing steps to increase the depth of penetration ofα-tocopherol into irradiated UHMWPE. Muratoglu et al. (see U.S.Provisional Application Ser. No. 60/709,795, filed Aug. 22, 2005)described annealing in supercritical carbon dioxide to increase depth ofpenetration of α-tocopherol into irradiated UHMWPE. UHMWPE medicalimplants can have a thickness of up to 30 mm and sometimes larger.Penetrating such large implants with α-tocopherol by diffusion can takea long time, however. Also, it is preferable in some embodiments todiffuse α-tocopherol into an irradiated UHMWPE preform and subsequentlymachine that preform to obtain the finished implant. The preform has tobe larger than the implant and therefore the diffusion path forα-tocopherol is increased.

A similar problem is often observed with polyethylene components thatare fabricated with an integral metal piece. Often the metal piece isporous to allow bone in-growth for the fixation of the implant. Inothers, the metal piece is not porous and may be used to increase thestructural integrity of the polyethylene piece. Therefore in thepresence of an integral metallic piece the diffusion of α-tocopherolwill either be slowed down near the surface covered with the porousmetals or inhibited near the surface covered by a non-porous metal plateor rod.

It can be beneficial to have α-tocopherol present throughout thepolymeric article to stabilize all free radicals and prevent long-termoxidation induced mechanical property changes.

In order to eliminate free radicals, several further methods can be usedsuch as melting (see Muratoglu et al. U.S. application Ser. No.10/757,551), mechanical deformation and recovery (see Muratoglu et al.,U.S. application Ser. No. 11/030,115) or high pressure crystallization(see Muratoglu et al. U.S. application Ser. No. 10/597,652).

In order to increase the strength of UHMWPE, high pressurecrystallization (HPC) of UHMWPE has been proposed. (See Bistolfi et al.,Transactions of the Orthopaedic Research Society, 2005. 240; Oral etal., Transactions of the Orthopaedic Research Society, 2005. p. 988;Muratoglu et al. U.S. Provisional Application No. 60/541,073, filed Feb.3, 2004; and PCT/US2005/003305, filed Feb. 3, 2005). High pressurecrystallization of unirradiated GUR1050 UHMWPE at above 160° C. and 300MPa yielded an approximately 70% crystalline UHMWPE, compared to 50-60%for conventional UHMWPE. This is due to a phase transition of the UHMWPEcrystals from the orthorhombic to the hexagonal phase at hightemperatures and pressures as discussed above. In the hexagonal phasecrystals grow to larger sizes and crystallinity increases (see Bassettet al., J Appl. Phys., 1974, 45(10): p. 4146-4150).

It can be advantageous to have α-tocopherol present throughout all orpart of the polymeric article in order to stabilize all free radicalsand prevent long-term oxidation induced mechanical property changes. Italso can be advantageous to have a medical implant, or any polymericcomponent thereof; doped with a spatial control of antioxidantdistribution. This spatial control can be achieved by having gradualchanges or step changes in the concentration of antioxidant. It also canbe advantageous to have a medical implant with a spatial control ofcross-linking. For example, Muratoglu et al. (see U.S. application Ser.No. 10/433,987, filed on Dec. 11, 2001) describe a UHMWPE with gradientcross-linking perpendicular to the irradiation direction by shielding.

This application describes UHMWPE medical implants that have a spatialcontrol of cross-linking due to irradiation of UHMWPE containing aspatially controlled distribution of antioxidant.

High concentrations of antioxidants, for example, α-tocopherol, near thesurface of a polymeric material can lead to elution of α-tocopherol intothe joint space after implantation. α-tocopherol can elute out of theimplants over time, especially at the human joint temperature of about37.5° C. to 40° C. When stored in air or in water at 40° C., theirradiated and α-tocopherol-doped UHMWPE loses about 10% of theα-tocopherol over about the first six months. The presence of excessα-tocopherol in the joint space may possibly lead to an adversebiological response. In order to avoid such complication, α-tocopherolcan be extracted from the polymeric material prior to placement and/orimplantation into the body. In order to minimize the elution ofα-tocopherol in vivo, a suitable method is necessary to extract theα-tocopherol from the surface regions of an α-tocopherol-containingcross-linked oxidation-resistant polymeric material. However, suchachievement were not possible until the present invention.

SUMMARY OF THE INVENTION

The present invention relates generally to methods for cross-linkingpolymeric materials with spatial control of antioxidant distribution,and products produced thereby. More specifically, the invention relatesto methods of making oxidation resistant cross-linked polymeric materialby irradiating polymeric materials having a gradient of antioxidant, forexample, vitamin E. More specifically, the invention relates to methodsof manufacturing antioxidant-doped, non-oxidizing medical devicecontaining cross-linked polymeric material with a spatial distributionof antioxidant and cross-linking throughout the polymeric composition,for example, radiation cross-linked ultra-high molecular weightpolyethylene (UHMWPE) with a controlled distribution of antioxidant andmaterials used therein.

The invention also relates to extraction of antioxidants and methods formaking cross-linked oxidation-resistant polymeric materials. Methods forextraction of antioxidants, for example, vitamin E (α-tocopherol), fromantioxidant containing consolidated polymeric materials, materials thatcan be used therewith, and products obtainable thereby, are alsoprovided. The invention also provides methods of makingoxidation-resistant cross-linked polymeric material by irradiating aconsolidated polymeric material, doping the consolidated polymericmaterial with an antioxidant, for example, vitamin E, and subsequentlyeluting or diffusing out a portion of the antioxidant from thecross-linked antioxidant-containing consolidated polymeric material,thereby preventing or minimizing in vivo elution of the antioxidant.More specifically, the invention also relates to methods ofmanufacturing antioxidant-doped, non-oxidizing medical device containingcross-linked polymeric material by eluting or diffusing out theantioxidant from the surface regions of the cross-linkedantioxidant-containing consolidated polymeric composition prior toplacement and/or implantation in the body, for example,antioxidant-doped irradiation cross-linked ultra-high molecular weightpolyethylene (UHMWPE), materials that can be used therein, and productsobtainable thereby.

In one embodiment, the invention provides methods of making anoxidation-resistant cross-linked polymeric material comprising: a)doping a consolidated polymeric material with an antioxidant bydiffusion below or above the melting point of the polymeric material,wherein the surface (exterior regions) of the polymeric material iscontacted with a lower concentration of antioxidant and bulk (generallythe interior regions) of the polymeric material is contacted with ahigher concentration of antioxidant than the surface, thereby allowing aspatial distribution of the antioxidant-rich and antioxidant-poorregions; and b) irradiating the consolidated polymeric materialcontaining the spatially distributed antioxidant with ionizingradiation, thereby forming an oxidation-resistant cross-linked polymericmaterial having a spatially controlled antioxidant distribution and/orcross-linking.

In another embodiment, the invention provides methods of making anoxidation-resistant cross-linked polymeric material comprising: a)doping a consolidated polymeric material with an antioxidant bydiffusion below or above the melting point of the polymeric material,wherein the bulk (generally the interior regions) of the polymericmaterial is contacted with a lower concentration of antioxidant andsurface of the polymeric material is contacted with a higherconcentration of antioxidant than the surface, thereby allowing aspatial distribution of the antioxidant-rich and antioxidant-poorregions; and b) irradiating the consolidated polymeric materialcontaining the spatially distributed antioxidant with ionizingradiation, thereby forming an oxidation-resistant cross-linked polymericmaterial having a spatially controlled antioxidant distribution and/orcross-linking.

In another embodiment, the invention provides methods of making anoxidation-resistant cross-linked polymeric material comprising: a)doping a consolidated polymeric material with an antioxidant bydiffusion below or above the melting point of the polymeric material,wherein the surface (exterior regions) of the polymeric materialcontains a lower concentration of antioxidant and bulk (generally theinterior regions) of the polymeric material contains a higherconcentration of antioxidant, thereby allowing a spatial distribution ofthe antioxidant-rich and antioxidant-poor regions; and b) irradiatingthe consolidated polymeric material containing the spatially distributedantioxidant with ionizing radiation, thereby forming anoxidation-resistant cross-linked polymeric material having a spatiallycontrolled antioxidant distribution and/or cross-linking.

In another embodiment, the invention provides methods of making anoxidation-resistant cross-linked polymeric material comprising: a)doping a consolidated polymeric material with an antioxidant bydiffusion below or above the melting point of the polymeric material,wherein the bulk of the polymeric material contains a lowerconcentration of antioxidant and surface of the polymeric materialcontains a higher concentration of antioxidant, thereby allowing aspatial distribution of the antioxidant-rich and antioxidant-poorregions; and b) irradiating the consolidated polymeric materialcontaining the spatially distributed antioxidant with ionizingradiation, thereby forming an oxidation-resistant cross-linked polymericmaterial having a spatially controlled antioxidant distribution and/orcross-linking.

In another embodiment, the invention provides methods of making anoxidation-resistant cross-linked polymeric material comprising: a)doping a consolidated polymeric material with an antioxidant bydiffusion below or above the melting point of the polymeric material, b)homogenizing the antioxidant-doped polymeric material by heating tobelow or above the melt, thereby allowing a spatial distribution of theantioxidant-rich and antioxidant-poor regions; and c) irradiating theconsolidated polymeric material containing the spatially distributedantioxidant with ionizing radiation, thereby forming anoxidation-resistant cross-linked polymeric material having a spatiallycontrolled antioxidant distribution and/or cross-linking.

In another embodiment, the invention provides methods of making anoxidation-resistant cross-linked polymeric material comprising: a)doping a consolidated polymeric material with an antioxidant bydiffusion below or above the melting point of the polymeric material, b)homogenizing the antioxidant-doped polymeric material by heating tobelow or above the melt, thereby allowing a spatial distribution of theantioxidant-rich and antioxidant-poor regions; and c) irradiating theconsolidated polymeric material containing the spatially distributedantioxidant with ionizing radiation, thereby forming anoxidation-resistant cross-linked polymeric material having a spatiallycontrolled antioxidant distribution and/or cross-linking.

In another embodiment, the invention provides methods of making amedical implant comprising an oxidation-resistant cross-linked polymericmaterial comprising: a) doping a consolidated polymeric material with anantioxidant by diffusion below or above the melting point of thepolymeric material, wherein the surface of the polymeric material iscontacted with a lower concentration of antioxidant and bulk of thepolymeric material is contacted with higher concentration ofantioxidant, thereby allowing a spatial distribution of theantioxidant-rich and antioxidant-poor regions; b) irradiating theconsolidated polymeric material containing the spatially distributedantioxidant with ionizing radiation, thereby forming a cross-linkedpolymeric material having a spatial distribution of oxidation-resistantregions; and c) machining the consolidated and antioxidant-dopedcross-linked polymeric material, thereby forming a medical implanthaving a spatially controlled distribution of oxidation-resistantregions. The medical implant can be packaged and sterilized.

In another embodiment, the invention provides methods of making amedical implant comprising an oxidation-resistant cross-linked polymericmaterial comprising: a) doping a consolidated polymeric material with anantioxidant by diffusion below or above the melting point of thepolymeric material, wherein the bulk of the polymeric material iscontacted with a lower concentration of antioxidant and surface of thepolymeric material is contacted with higher concentration ofantioxidant, thereby allowing a spatial distribution of theantioxidant-rich and antioxidant-poor regions; b) irradiating theconsolidated polymeric material containing the spatially distributedantioxidant with ionizing radiation, thereby forming a cross-linkedpolymeric material having a spatial distribution of oxidation-resistantregions; and c) machining the consolidated and antioxidant-dopedcross-linked polymeric material, thereby forming a medical implanthaving a spatially controlled distribution of oxidation-resistantregions. The medical implant can be packaged and sterilized. In anotherembodiment, the invention provides methods of making a medical implantcomprising an oxidation-resistant cross-linked polymeric materialcomprising: a) doping a consolidated polymeric material with anantioxidant by diffusion below or above the melting point of thepolymeric material, wherein the surface of the polymeric materialcontains a lower concentration of antioxidant and bulk of the polymericmaterial contains higher concentration of antioxidant, thereby allowinga spatial distribution of the antioxidant-rich and antioxidant-poorregions; b) irradiating the consolidated polymeric material containingthe spatially distributed antioxidant with ionizing radiation, therebyforming a cross-linked polymeric material having a spatial distributionof oxidation-resistant regions; and c) machining the consolidated andantioxidant-doped cross-linked polymeric material, thereby forming amedical implant having a spatially controlled distribution ofoxidation-resistant regions. The medical implant can be packaged andsterilized.

In another embodiment, the invention provides methods of making amedical implant comprising an oxidation-resistant cross-linked polymericmaterial comprising: a) doping a consolidated polymeric material with anantioxidant by diffusion below or above the melting point of thepolymeric material, wherein the bulk of the polymeric material containsa lower concentration of antioxidant and surface of the polymericmaterial contains higher concentration of antioxidant, thereby allowinga spatial distribution of the antioxidant-rich and antioxidant-poorregions; b) irradiating the consolidated polymeric material containingthe spatially distributed antioxidant with ionizing radiation, therebyforming a cross-linked polymeric material having a spatial distributionof oxidation-resistant regions; and c) machining the consolidated andantioxidant-doped cross-linked polymeric material, thereby forming amedical implant having a spatially controlled distribution ofoxidation-resistant regions. The medical implant can be packaged andsterilized.

In another embodiment, the invention provides methods of making amedical implant comprising an oxidation-resistant cross-linked polymericmaterial comprising: a) doping a consolidated polymeric material with anantioxidant by diffusion below or above the melting point of thepolymeric material, b) homogenizing the antioxidant-doped polymericmaterial by heating to below or above the melt, thereby allowing aspatial distribution of the antioxidant-rich and antioxidant-poorregions; c) irradiating the consolidated polymeric material containingthe spatially distributed antioxidant with ionizing radiation, therebyforming a cross-linked polymeric material having a spatial distributionof oxidation-resistant regions; and d) machining the consolidated andantioxidant-doped cross-linked polymeric material, thereby forming amedical implant having a spatially controlled distribution ofoxidation-resistant regions. The medical implant can be packaged andsterilized.

In another embodiment, the invention provides methods of making anoxidation-resistant cross-linked polymeric material comprising: a)blending a polymeric material with an antioxidant, wherein a portion ofthe polymeric material is contacted with a lower concentration ofantioxidant and portion of the polymeric material is contacted with ahigher concentration of antioxidant, thereby allowing a spatialdistribution of the antioxidant-rich and antioxidant-poor regions; b)consolidating the antioxidant blended polymeric material, therebyforming a medical implant preform; and c) irradiating the medicalimplant preform containing the spatially distributed antioxidant withionizing radiation, thereby forming a medical implant preform having anoxidation-resistant cross-linked polymeric material having a spatiallycontrolled cross-linking and antioxidant distribution.

In another embodiment, the invention provides methods of making amedical implant comprising an oxidation-resistant cross-linked polymericmaterial comprising: a) blending a polymeric material with anantioxidant, wherein a first portion of the polymeric material iscontacted with a lower concentration of antioxidant and a second portionof the polymeric material is contacted with a higher concentration ofantioxidant than the first portion, thereby allowing a spatialdistribution of the antioxidant-rich and antioxidant-poor regions; b)consolidating the antioxidant blended polymeric material, therebyforming a medical implant preform; c) irradiating the medical implantpreform containing the spatially distributed antioxidant with ionizingradiation, thereby forming an oxidation-resistant cross-linked medicalimplant preform having a spatially controlled antioxidant distribution;and d) machining the oxidation-resistant cross-linked medical implantpreform having the spatially controlled antioxidant distribution,thereby forming an oxidation-resistant cross-linked medical implanthaving a spatially controlled antioxidant distribution and/orcross-linking. The medical implant can be packaged and sterilized.

In another embodiment, the invention provides methods of making amedical implant comprising an oxidation-resistant cross-linked polymericmaterial comprising: a) blending a polymeric material with anantioxidant, wherein a first portion of the polymeric material containsa lower concentration of antioxidant and a second portion of thepolymeric material contains a higher concentration of antioxidant thanthe first portion, thereby allowing a spatial distribution of theantioxidant-rich and antioxidant-poor regions; b) consolidating theantioxidant blended polymeric material, thereby forming a medicalimplant preform; c) irradiating the medical implant preform containingthe spatially distributed antioxidant with ionizing radiation, therebyforming an oxidation-resistant cross-linked medical implant preformhaving a spatially controlled antioxidant distribution; and d) machiningthe oxidation-resistant cross-linked medical implant preform having thespatially controlled antioxidant distribution, thereby forming anoxidation-resistant cross-linked medical implant having a spatiallycontrolled antioxidant distribution and/or cross-linking. The medicalimplant can be packaged and sterilized.

In another embodiment, the invention provides methods of making amedical implant comprising an oxidation-resistant cross-linked polymericmaterial comprising: a) blending a polymeric material with anantioxidant, wherein a first portion of the polymeric material iscontacted with a lower concentration of antioxidant and a second portionof the polymeric material is contacted with a higher concentration ofantioxidant than the first portion, thereby allowing a spatialdistribution of the antioxidant-rich and antioxidant-poor regions; b)consolidating the antioxidant blended polymeric material, therebyforming a medical implant preform; c) machining the medical implantpreform having a spatial distribution of antioxidant, thereby forming anoxidation-resistant medical implant having a spatially controlledantioxidant distribution; and d) irradiating the oxidation-resistantmedical implant preform containing the spatially distributed antioxidantwith ionizing radiation, thereby forming an oxidation-resistantcross-linked medical implant having a spatially controlled antioxidantdistribution and/or cross-linking. The medical implant can be packagedand sterilized.

In another embodiment, the invention provides methods of making amedical implant comprising: a) blending one or more types of resin,flakes, or powder with different concentrations of an antioxidant,wherein a first portion of the resin, flakes, or powder are contactedwith a lower concentration of antioxidant and a second portion of theresin, flakes, or powder are contacted with a higher concentration ofantioxidant than the first portion, thereby allowing a spatialdistribution of the antioxidant-rich and antioxidant-poor regions; b)consolidating the antioxidant-blended resin, flakes, or powder, therebyforming a medical implant preform; c) irradiating theoxidation-resistant medical implant perform containing the spatiallydistributed antioxidant with ionizing radiation, thereby forming anoxidation-resistant medical implant preform having a spatiallycontrolled cross-linking and antioxidant distribution; and d) machiningthe medical implant preform having a spatial distribution ofcross-linking and antioxidant, thereby forming an oxidation-resistantmedical implant having a spatially controlled cross-linking andantioxidant distribution. The medical implant can be packaged andsterilized.

In another embodiment, the invention provides methods of making amedical implant comprising: a) blending two or more types of resin,flakes, or powder with different concentrations of an antioxidant,wherein a portion of the resin, flakes, or powder are contacted with alower concentration of antioxidant and portion of the resin, flakes, orpowder are contacted with a higher concentration of antioxidant, therebyallowing a spatial distribution of the antioxidant-rich andantioxidant-poor regions; b) consolidating the antioxidant-blendedresin, flakes, or powder, thereby forming a medical implant preform; c)irradiating the oxidation-resistant medical implant preform containingthe spatially distributed antioxidant with ionizing radiation, therebyforming an oxidation-resistant medical implant preform having aspatially controlled cross-linking and antioxidant distribution; and d)machining the medical implant preform having a spatial distribution ofcross-linking and antioxidant, thereby forming an oxidation-resistantmedical implant having a spatially controlled cross-linking andantioxidant distribution. The medical implant can be packaged andsterilized.

In another embodiment, the invention provides methods of making amedical implant comprising: a) blending one or more types of resin,flakes, or powder with different concentrations of an antioxidant,wherein a portion of the resin, flakes, or powder are contacted with alower concentration of antioxidant and portion of the resin, flakes, orpowder are contacted with a higher concentration of antioxidant, therebyallowing a spatial distribution of the antioxidant-rich andantioxidant-poor regions; b) consolidating the antioxidant-blendedresin, flakes, or powder, thereby forming a medical implant preform; c)machining the medical implant preform having a spatial distribution ofantioxidant, thereby forming an oxidation-resistant medical implanthaving a spatially controlled antioxidant distribution; and d)irradiating the oxidation-resistant medical implant containing thespatially distributed antioxidant with ionizing radiation, therebyforming an oxidation-resistant medical implant having a spatiallycontrolled cross-linking and antioxidant distribution. The medicalimplant can be packaged and sterilized.

In some embodiments, the medical implant preform is irradiated andsubsequently machined to obtain the final medical implant shape. In someembodiments, the blends of resin, flakes, or powder contain the sameconcentration of antioxidant.

According to another embodiment, the invention provides methods ofmaking a medical implant as described in various embodiments, whereinthe surface of the polymeric material is contacted with no or lowconcentration of antioxidant and bulk of the polymeric material iscontacted with a higher concentration of antioxidant.

In one embodiment, the invention provides methods of making anoxidation-resistant cross-linked polymeric material, wherein across-linked polymeric material having a spatially controlledantioxidant distribution and/or cross-linking can be further treated by:a) heating to above the melting point of the polymeric material; b)pressurizing the heated polymeric material to at least 0.001-1000 MPa;c) keeping at this pressure and temperature; d) cooling down to belowthe melting point of the polymeric material under pressure; and e)releasing the pressure to about ambient pressure.

In another embodiment, the invention provides methods of making anoxidation-resistant cross-linked polymeric material comprising, whereina cross-linked polymeric material having a spatially controlledantioxidant distribution and/or cross-linking can be further treated by:a) pressurizing the polymeric material to at least 0.001-1000 MPa; b)heating the pressurized polymeric material to below the melting point ofthe pressurized polymeric material; c) keeping at this pressure andtemperature; d) cooling down to below the melting point of the polymericmaterial under pressure; and e) releasing the pressure to about ambientpressure.

In another embodiment, the invention provides methods of making anoxidation-resistant cross-linked polymeric material comprising: a)blending a polymeric material with an antioxidant; b) consolidating theantioxidant-blended polymeric material, thereby forming anoxidation-resistant polymeric material; c) irradiating the consolidatedoxidation-resistant polymeric material with ionizing radiation, therebyforming an oxidation-resistant cross-linked polymeric material; and d)extracting or eluting the antioxidant from the surface regions of theoxidation-resistant cross-linked polymeric material, thereby preventingor minimizing in vivo elution of the antioxidant.

In another embodiment, the invention provides methods of making amedical implant comprising an oxidation-resistant cross-linked medicalimplant comprising: a) blending a polymeric material with anantioxidant; b) consolidating the antioxidant-blended polymericmaterial, thereby forming an oxidation-resistant consolidated polymericmaterial; c) irradiating the consolidated oxidation-resistant polymericmaterial with ionizing radiation, thereby forming an oxidation-resistantcross-linked consolidated polymeric material; d) machining theconsolidated and antioxidant-resistant cross-linked polymeric material,thereby forming an oxidation-resistant cross-linked medical implanthaving oxidation-resistant regions; and e) extracting or eluting theantioxidant from the surface regions of the oxidation-resistantcross-linked medical implant prior to placement and/or implantation intothe body, thereby preventing or minimizing in vivo elution of theantioxidant from the oxidation-resistant cross-linked medical implant.The medical implant can be packaged and sterilized.

In another embodiment, the invention provides methods of making anoxidation-resistant cross-linked medical implant preform comprising: a)blending a polymeric material with an antioxidant; b) consolidating theantioxidant-blended polymeric material, thereby forming anoxidation-resistant medical implant preform; c) irradiating theoxidation-resistant medical implant preform with ionizing radiation,thereby forming a medical implant preform having an oxidation-resistantcross-linked polymeric material; and d) extracting or eluting theantioxidant from the surface regions of the oxidation-resistantcross-linked medical implant preform, thereby preventing or minimizingin vivo elution of the antioxidant. The medical implant can be packagedand sterilized.

In another embodiment, the invention provides methods of making amedical implant comprising an oxidation-resistant cross-linked medicalimplant comprising: a) blending a polymeric material with anantioxidant; b) consolidating the antioxidant-blended polymericmaterial, thereby forming an oxidation-resistant consolidated polymericmaterial; c) machining the consolidated and antioxidant-resistantpolymeric material, thereby forming an oxidation-resistant medicalimplant; d) irradiating the oxidation-resistant medical implant withionizing radiation, thereby forming an oxidation-resistant cross-linkedmedical implant; and e) extracting or eluting the antioxidant from thesurface regions of the oxidation-resistant cross-linked medical implantprior to placement and/or implantation into the body, thereby preventingor minimizing in vivo elution of the antioxidant from theoxidation-resistant cross-linked medical implant. The medical implantcan be packaged and sterilized.

In another embodiment, the invention provides methods of making anoxidation-resistant cross-linked polymeric material comprising: a)doping a consolidated polymeric material with an antioxidant below orabove the melting point of the polymeric material, thereby forming anoxidation-resistant polymeric material; b) irradiating the consolidatedoxidation-resistant polymeric material with ionizing radiation, therebyforming an oxidation-resistant cross-linked consolidated polymericmaterial; and c) extracting or eluting the antioxidant from the surfaceregions of the oxidation-resistant cross-linked consolidated polymericmaterial, thereby preventing or minimizing in vivo elution of theantioxidant.

In another embodiment, the invention provides methods of making anoxidation-resistant cross-linked medical implant comprising: a) doping aconsolidated polymeric material with an antioxidant above or below themelting point of the polymeric material, thereby forming anoxidation-resistant polymeric material; b) irradiating the consolidatedoxidation-resistant polymeric material with ionizing radiation, therebyforming an oxidation-resistant cross-linked consolidated polymericmaterial; c) machining the consolidated and antioxidant-resistantpolymeric material, thereby forming an oxidation-resistant cross-linkedmedical implant; and d) extracting or eluting the antioxidant from thesurface regions of the oxidation-resistant cross-linked medical implantprior to placement and/or implantation into the body, thereby preventingor minimizing in vivo elution of the antioxidant. The medical implantcan be packaged and sterilized.

In another embodiment, the invention provides methods of making anoxidation-resistant cross-linked polymeric material comprising: a)blending a polymeric material with an antioxidant; b) consolidating theantioxidant-blended polymeric material, thereby forming anoxidation-resistant polymeric material; c) extracting or eluting theantioxidant from the surface regions of the oxidation-resistantpolymeric material, thereby preventing or minimizing in vivo elution ofthe antioxidant; and d) irradiating the consolidated oxidation-resistantpolymeric material with ionizing radiation, thereby forming anoxidation-resistant cross-linked polymeric material.

In another embodiment, the invention provides methods of making amedical implant comprising an oxidation-resistant cross-linked medicalimplant comprising: a) blending a polymeric material with anantioxidant; b) consolidating the antioxidant-blended polymericmaterial, thereby forming an oxidation-resistant consolidated polymericmaterial; c) extracting or eluting the antioxidant from the surfaceregions of the oxidation-resistant consolidated polymeric material,thereby preventing or minimizing in vivo elution of the antioxidant fromthe consolidated polymeric material; d) irradiating the consolidatedoxidation-resistant polymeric material with ionizing radiation, therebyforming an oxidation-resistant cross-linked consolidated polymericmaterial; and e) machining the consolidated and antioxidant-resistantcross-linked polymeric material, thereby forming an oxidation-resistantcross-linked medical implant. The medical implant can be packaged andsterilized.

In another embodiment, the invention provides methods of making anoxidation-resistant cross-linked medical implant preform comprising: a)blending a polymeric material with an antioxidant; b) consolidating theantioxidant-blended polymeric material, thereby forming anoxidation-resistant medical implant preform; c) extracting or elutingthe antioxidant from the surface regions of the oxidation-resistantpolymeric material, thereby preventing or minimizing in vivo elution ofthe antioxidant; d) irradiating the oxidation-resistant medical implantpreform with ionizing radiation, thereby forming a medical implantpreform having an oxidation-resistant cross-linked polymeric material.The medical implant can be packaged and sterilized.

In another embodiment, the invention provides methods of making amedical implant comprising an oxidation-resistant cross-linked medicalimplant comprising: a) blending the polymeric material with anantioxidant; b) consolidating the antioxidant-blended polymericmaterial, thereby forming an oxidation-resistant consolidated polymericmaterial; c) machining the consolidated and antioxidant-resistantpolymeric material, thereby forming an oxidation-resistant medicalimplant; d) extracting or eluting the antioxidant from the surfaceregions of the oxidation-resistant medical implant, thereby preventingor minimizing in vivo elution of the antioxidant from theoxidation-resistant medical implant; and e) irradiating theoxidation-resistant medical implant with ionizing radiation, therebyforming an oxidation-resistant cross-linked medical implant. The medicalimplant can be packaged and sterilized.

In another embodiment, the invention provides methods of making anoxidation-resistant cross-linked polymeric material comprising: a)doping a consolidated polymeric material with an antioxidant above orbelow the melting point of the polymeric material, thereby forming anoxidation-resistant polymeric material; b) extracting or eluting theantioxidant from the surface regions of the oxidation-resistantconsolidated polymeric material, thereby preventing or minimizing invivo elution of the antioxidant; and c) irradiating the consolidatedoxidation-resistant polymeric material with ionizing radiation, therebyforming an oxidation-resistant cross-linked consolidated polymericmaterial.

In another embodiment, the invention provides methods of making anoxidation-resistant cross-linked medical implant comprising: a) doping aconsolidated polymeric material with an antioxidant, thereby forming anoxidation-resistant polymeric material; b) machining the consolidatedand antioxidant-resistant polymeric material, thereby forming anoxidation-resistant medical implant; c) extracting or eluting theantioxidant from the surface regions of the oxidation-resistant medicalimplant, thereby preventing or minimizing in vivo elution of theantioxidant; and d) irradiating the oxidation-resistant medical implantwith ionizing radiation, thereby forming an oxidation-resistantcross-linked medical implant. The medical implant can be packaged andsterilized.

In another embodiment, the invention provides methods of making anoxidation-resistant cross-linked medical implant comprising: a) blendingone or more types of resin, flakes, or powder with an antioxidant; b)consolidating the antioxidant-blended resin, flakes, or powder, therebyforming a medical implant preform; c) extracting or eluting theantioxidant from the surface regions of the oxidation-resistant medicalimplant preform, thereby preventing or minimizing in vivo elution of theantioxidant; d) irradiating the oxidation-resistant medical implantpreform with ionizing radiation, thereby forming an oxidation-resistantcross-linked medical implant preform; and e) machining theoxidation-resistant cross-linked medical implant perform, therebyforming an oxidation-resistant cross-linked medical implant. The medicalimplant can be packaged and sterilized.

In another embodiment, the antioxidant-doped or -blended polymericmaterial is homogenized at a temperature below or above the meltingpoint of the polymeric material for about an hour to several days.

In another embodiment of the invention, the oxidation-resistantcross-linked medical implant preform is further homogenized followingthe irradiation step by heating to a temperature below or above the meltto allow diffusion of the antioxidant from the antioxidant-rich toantioxidant-poor regions and oxidative stability throughout the medicalimplant.

According to one embodiment of the invention, the oxidation-resistantpolymeric material or the medical implant is further doped with anantioxidant by diffusion at a temperature below or above the meltingpoint of the irradiated polymeric material.

In another embodiment, the antioxidant-doped or -blended polymericmaterial is further homogenized at a temperature below or above themelting point of the polymeric material for about an hour to severaldays to several weeks.

In another embodiment, the antioxidant-doped or -blended polymericmaterial, the oxidation-resistant medical implant preform, or themedical implant preform is further homogenized at a temperature below orabove the melting point of the polymeric material, before and/or afterthe irradiation step, for about an hour to several days to severalweeks.

In another embodiment, the antioxidant-doped or -blended polymericmaterial is machined thereby creating a medical implant.

In another embodiment, the medical implant is packaged and sterilized byionizing radiation or gas sterilization, thereby forming a sterile andcross-linked oxidation-resistant medical implant.

In some embodiments, the polymeric material is compression molded toanother piece or a medical implant, thereby forming an interface or aninterlocked hybrid material; or the antioxidant blended polymericmaterial is compression molded to another piece or a medical implant,thereby forming an interface or an interlocked hybrid material; or theconsolidated antioxidant doped polymeric material is compression moldedto another piece, thereby forming an interface and an interlocked hybridmaterial; or the consolidated polymeric material is compression moldedto another piece, thereby forming an interface and an interlocked hybridmaterial.

In another embodiment, irradiated and melted material is compressionmolded onto the surface of the antioxidant-doped or -blended polymericmaterial or implant. In another embodiment, irradiated, mechanicallydeformed and thermally treated (above or below the melt) material iscompression molded onto the surface of the anti-oxidant doped or blendedpolymeric material or implant. In another embodiment, irradiated andhigh pressure crystallized polymeric material is compression molded ontothe surface of the antioxidant-doped or -blended polymeric material orimplant.

In another embodiment, the invention provides an oxidation-resistantcross-linked polymeric material having a spatially controlledantioxidant distribution, wherein the polymeric material is obtainableby any of the methods described herein.

According to one aspect of the invention, the doping is carried out bysoaking the medical implant in the antioxidant, preferably, for abouthalf an hour to about 100 hours, more preferably, for about an hour,about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or about 16 hours,and/or the antioxidant is heated to about 120° C. and the doping iscarried out at about 120° C., and/or the antioxidant is warmed to aboutroom temperature and the doping is carried out at room temperature or ata temperature between room temperature and the peak melting temperatureof the polymeric material or less than about 137° C., and/or thecross-linked polymeric material is heated at a temperature below themelt or above the melt of the cross-linked polymeric material.

According to another aspect of the invention, the polymeric material isa polyolefin, a polypropylene, a polyamide, a polyether ketone, or amixture thereof; wherein the polyolefin is selected from a groupconsisting of a low-density polyethylene, high-density polyethylene,linear low-density polyethylene, ultra-high molecular weightpolyethylene (UHMWPE), or a mixture thereof; and wherein the polymericmaterial is polymeric resin powder, polymeric flakes, polymericparticles, or the like, or a mixture thereof or a consolidated resin.

According to another aspect of the invention, polymeric material is ahydrogel, such as poly (vinyl alcohol), poly (acrylamide), poly (acrylicacid), poly(ethylene glycol), blends thereof, or interpenetratingnetworks thereof, which can absorb water such that water constitutes atleast 1 to 10,000% of their original weight, typically 100 wt % of theiroriginal weight or 99% or less of their weight after equilibration inwater.

In another embodiment of the invention, the implant comprises medicaldevices selected from the group consisting of acetabular liner, shoulderglenoid, patellar component, finger joint component, ankle jointcomponent, elbow joint component, wrist joint component, toe jointcomponent, bipolar hip replacements, tibial knee insert, tibial kneeinserts with reinforcing metallic and polyethylene posts, intervertebraldiscs, interpositional devices for any joint, sutures, tendons, heartvalves, stents, vascular grafts.

In another embodiment of the invention, the medical implant is anon-permanent medical device, for example, a catheter, a ballooncatheter, a tubing, an intravenous tubing, or a suture.

In another embodiment of the invention, the oxidation-resistantcross-linked medical implant preform is further homogenized followingthe irradiation step by heating to a temperature below or above the meltto allow diffusion of the antioxidant from the antioxidant-rich toantioxidant-poor regions and oxidative stability throughout the medicalimplant.

In another embodiment of the invention, the antioxidant-doped polymericmaterial, the oxidation-resistant medical implant preform, or themedical implant preform is homogenized before and/or after irradiation,by thermally annealing at a temperature above or below the melting pointof the polymeric material.

In another embodiment of the invention, the cross-linkedoxidation-resistant medical implant is packaged and sterilized byionizing radiation or gas sterilization, thereby forming a sterile andoxidation-resistant cross-linked medical implant having a spatialdistribution of antioxidant and/or cross-linking.

In another embodiment of the invention, the antioxidant is diffused to adepth of about 5 mm or more from the surface, for example, to a depth ofabout 3-5 mm, about 1-3 mm, or to any depth thereabout or therebetween.

In another embodiment, the invention provides an oxidation-resistantcross-linked polymeric material obtainable by any of the methodsdescribed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows schematic diagram of direct compression molding (DCM) ofUHMWPE with Vitamin E rich and Vitamin E poor regions.

FIG. 2 shows schematic diagram of DCM of UHMWPE containing integralmetal piece.

FIG. 3A shows a 1.5″ thick UHMWPE puck. The puck was made from half GUR1050 blended with 0.5 wt % α-tocopherol and half virgin GUR 1050 powder(1.5″ thick and 2.5″ in diameter). The light brown half on the leftcontains α-tocopherol.

FIG. 3B illustrates a plot of Vitamin E Index (VEI) vs. depth (measuredthrough the thickness of the puck). There is a smooth transition fromconstant Vitamin E content at the left side of the plot to virgin UHMWPEon the right side of the plot. The transition occurs over a relativelysmall range of 3 min.

FIG. 4A shows Vitamin E Index (VEI) for 1.5″ thick UHMWPE puck made withboth α-tocopherol containing UHMWPE powder and virgin UHMWPE powderbefore and after irradiation.

FIG. 4B shows VEI for 1″ thick UHMWPE puck made with both α-tocopherolcontaining UHMWPE powder and virgin UHMWPE powder before and afterirradiation.

FIG. 5 depicts FTIR spectra for UHMWPE highlighting the differencebetween aged UHMWPE with and without α-tocopherol.

FIG. 6A shows Oxidation index ((DI), Vitamin E Index (VEI), and VitaminE Quinone Index (VEQI) for a 1.5″ UHMWPE puck that was subjected toannealing and aging. The trend between VEI and VEQI is notable ascompared to FIG. 6B.

FIG. 6B shows Oxidation index (OI), Vitamin E Index (VEI), and Vitamin EQuinone index (VEQI) for a 1″ UHMWPE puck that was subjected to doping,homogenization, and aging. The trend between VEI and VEQI is notable ascompared to FIG. 6A.

FIG. 7 illustrates the peak associated with Vitamin E quinone at 1680cm⁻¹ as a function of depth.

FIG. 8 shows the cross-link density of vitamin E-blended andsubsequently irradiated UHMWPE as a function of radiation dose andvitamin E concentration.

FIGS. 9A-9C show the ultimate tensile strength (UTS),elongation-at-break (EAB), and work-to-failure (WF) of vitamin E blendedand subsequently irradiated UHMWPE as a function of radiation dose andvitamin E concentration.

FIG. 10 shows vitamin E index and transvinylene index (TVI) of UHMWPEdoped with vitamin E and subsequently irradiated. The graph shows theconcentration profile before irradiation and TVI profile after 100-kGyirradiation of a GUR1050 UHMWPE block, whose surface was doped for 15minutes by placing in a vitamin E bath at 170° C.

FIGS. 11A & 11B show the vitamin E concentration profile of a UHMWPEthin section melt-doped at 170° C. for 22 hours and subsequentlyhomogenized at 132° C. for 48 hours. FIG. 11A shows vitamin Econcentration profiles of unirradiated UHMWPE doped with vitamin E at120° C. for 2, 8 and 24 hours. FIG. 11B shows Vitamin E concentrationprofiles of 65-kGy irradiated UHMWPE doped with vitamin E at 120° C. for2, 8 and 24 hours.

FIG. 12 illustrates vitamin E concentration profiles of 100-kGyirradiated UHMWPE doped at 120° C. for 6 hours and homogenized at 130°C. for 50 or 216 hours.

FIGS. 13A & 13 B show the free radical signals as measured by electronspin resonance of 65-kGy and 100-kGy UHMWPE controls and high pressureannealed samples.

FIG. 14 shows schematic diagram of extraction of α-tocopherol from adoped UHMWPE.

FIGS. 15A & 15B show diffusion of α-tocopherol 100 kGy irradiated UHMWPEas a function of temperature for 24 hours, and as a function of time at105° C.

FIG. 16 shows a comparison of α-tocopherol concentration profiles of 85kGy irradiated UHMWPE doped at 120° C. for 4 hours and of 85 kGyirradiated UHMWPE doped at 120° C. for 4 hours followed byhomogenization at 120° C. for 24 hours.

FIG. 17 depicts vitamin E concentration profiles of 1.0 wt %α-tocopherol-blended UHMWPE before and after 100 kGy gamma irradiation.

FIG. 18 shows vitamin E concentration profiles of vitamin E-blended andsubsequently irradiated UHMWPE before and after extraction in boilingethanol for 16 hours.

FIG. 19 shows vitamin E concentration profiles of vitamin E-blendedUHMWPE

FIG. 20 illustrates vitamin E concentration profiles of 100-kGyirradiated UHMWPE doped and homogenized at 120° C. before and afterextraction in a surfactant solution and emulsion under self-generatedpressure at 120° C. for 20 hours.

FIG. 21 illustrates vitamin E concentration profiles of 100-kGyirradiated UHMWPE doped and homogenized at 120° C. before and afterextraction at ambient pressure at boiling temperature under reflux.

FIG. 22 shows vitamin E concentration profiles of 85-kGy irradiated,doped, homogenized and sterilized acetabular liners before and afterboiling hexane extraction for 72 hours.

FIG. 23 depicts average surface oxidation indices of 85-kGy irradiatedUHMWPE and 85-kGy irradiated, α-tocopherol doped UHMWPE after hexaneextraction, accelerated bomb aging and accelerated oven aging.

FIG. 24 depicts average bulk oxidation indices of 85-kGy irradiatedUHMWPE and 85-kGy irradiated, α-tocopherol doped UHMWPE after hexaneextraction, accelerated bomb aging and accelerated oven aging.

FIG. 25 shows vitamin E concentration profiles for preforms (6.8 mmthick), 2.6 mm-thick liners machined from these preforms and 2.6mm-thick liners after sterilization. The profiles are splined averagesof three separate samples.

FIG. 26 depicts the vitamin E concentration profiles of vitamin E dopedand homogenized liners before and after extraction by a surfactantemulsion.

FIG. 27 shows vitamin E and oxidation profile of 100-kGy irradiatedUHMWPE doped for 48 hours at 100° C.

FIG. 28 illustrates the oxidation profiles of vitamin E-blended and200-kGy irradiated UHMWPE.

FIG. 29 demonstrates vitamin E concentration profiles of highlycross-linked, doped, homogenized and sterilized UHMWPE real-time aged atroom temperature on the shelf.

FIG. 30 demonstrates vitamin E concentration profiles of highlycross-linked, doped, homogenized and sterilized UHMWPE real-time aged at40° C. in air.

FIG. 31 demonstrates vitamin E concentration profiles of highlycross-linked, doped, homogenized and sterilized UHMWPE real-time aged at40° C. in water.

FIGS. 32A & 32B show compression molding of UHMWPE resin containing twodifferent concentrations of vitamin E and the resulting molded UHMWPEblock with a spatially controlled gradient in vitamin E concentration.

FIG. 33 shows vitamin E concentration of UHMWPE blocks containing agradient of vitamin E concentration from 0.05 wt % to 0.5 wt % vitamin Eas a function of depth. The dotted lines denote the beginning and end ofthe gradient; to the left of the dotted lines is a homogeneous portionof the sample containing 0.05 wt % vitamin E and to the right of thedotted lines is the homogeneous portion of the sample containing 0.5 wt% vitamin E.

FIG. 34 illustrates cross-link density of the irradiated UHMWPE block atdifferent spatial locations containing different amounts of vitamin E;namely 0.5 wt % vitamin E, within the span of the gradient from 0.5 wt %to 0.05 wt % vitamin E and 0.05 wt % vitamin E. The schematic on theupper left side shows the locations at which cross-link densitymeasurements were made.

FIG. 35 shows ultimate tensile strength of gradient cross-linked UHMWPE.The schematic on the left shows the stamping location of the tensiledog-bones and the testing direction. Separate UHMWPE molded blocks withhomogenous 0.05 wt % or 0.5 wt % vitamin E concentration were used ascontrols after irradiation.

FIG. 36 depicts a representative gradient cross-linked UHMWPE tensiletesting specimen before and after testing. The location of the failureand the different regions of the UHMWPE with different concentrations ofvitamin E are marked.

FIG. 37 shows tear strength of gradient cross-linked UHMWPE. Theschematic on the left shows the stamping location of the tear testspecimens and the testing direction. Separate UHMWPE molded blocks withhomogenous 0.05 wt % or 0.5 wt % vitamin E concentration were used ascontrols after irradiation.

FIGS. 38A & 38B schematically depict the location of machined pins withrespect to the gradient and the location of the wear surfaces of thepins with respect to the vitamin E concentration gradient determined byFTIR.

FIGS. 39A & 38B show gradient vitamin E profiles of molded vitaminE-blended UHMWPEs; strategies 1 and 2 with a thin film of moldedpolyethylene in between the powder, strategy 3.

FIGS. 40A & 40B illustrate[s] vitamin E profiles of 0.3 wt % (40 a) and0.5 wt % vitamin E-blended UHMWPE extracted in boiling hexane forvarious durations.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods for making cross-linkedoxidation-resistant polymeric materials and/or preventing or minimizingin vivo elution of antioxidant from the antioxidant-containing polymericmaterials. The invention pertains to methods of doping consolidatedpolymeric materials, such as UHMWPE, with a spatial control ofantioxidant distribution, for example, vitamin E, before, during, orafter radiation cross-linking the polymeric materials, as well asmaterials made thereby. The invention also pertains to methods ofextraction of antioxidants, for example, vitamin E (α-tocopherol), fromantioxidant-containing consolidated polymeric materials, includingcross-linked polymeric materials, as well as materials made thereby.

According to one aspect of the invention, the limitations ofα-tocopherol diffusion in polymeric material are overcome by shorteningthe diffusion path of α-tocopherol necessary after irradiation. This isachieved by creating a polymeric article that has higher α-tocopherolconcentration in the bulk (generally the interior regions) and lowerα-tocopherol concentration on the surface (exterior regions). When thispolymeric article is irradiated, the α-tocopherol-poor regions in thesurface, in which wear reduction through cross-linking is necessary, canbe as highly cross-linked as they would be in the absence ofα-tocopherol. On the other hand, the surface contains either noα-tocopherol or lower concentrations of α-tocopherol. Therefore, thesurface is cross-linked during irradiation and the wear rate is reduced.Cross-linking is only needed on and near the articular surfaces toimprove the wear resistance of the implant. Although the surface and thebulk of a polymeric material generally refer to exterior regions and theinterior regions, respectively, there generally is no discrete boundarybetween these two regions. The regions are more of a gradient-liketransition, can differ based upon the size and shape of the object andthe resin used.

Irradiation of UHMWPE with α-tocopherol reduces the cross-linkingefficiency of polyethylene and also reduces the anti-oxidant potency ofα-tocopherol. Therefore, in some embodiments, there is enoughα-tocopherol in the bulk such that after the irradiation step(s) thereis still enough anti-oxidant potency to prevent oxidation in the bulk ofthe polyethylene. Thus, after irradiation the polymeric article isoxidation-resistant in the bulk and is highly cross-linked on thesurface. However the surface may contain unstabilized free radicals thatcan oxidize and reduce the mechanical properties of the article. Toprevent oxidation on the α-tocopherol-poor surface region, theirradiated polymeric article can be treated by using one or more of thefollowing methods:

(1) doping with an antioxidant through diffusion at an elevatedtemperature below or above the melting point of the irradiated polymericmaterial;

(2) melting of the article;

(3) mechanically deforming of the UHMWPE followed by heating below orabove the melting point of the polymeric material; and

(4) high pressure crystallization or high pressure annealing of thearticle;

After these treatments, the free radicals are stabilized in the article.Doping of α-tocopherol through diffusion at a temperature above themelting point of the irradiated polymeric material (for example, at atemperature above 137° C. for UHMWPE) can be carried out undersub-ambient pressure, ambient pressure, elevated pressure, and/or in asealed chamber. Doping above the melting point can be done by soakingthe article in vitamin E at a temperature above 137° C. for at least 10seconds to about 100 hours or longer. At elevated pressures, the meltingpoint of polymeric material can be elevated, therefore temperatureranges ‘below’ and ‘above’ the melting point may change under pressure.

In some embodiments none of the above mentioned four stabilizationtechniques are used because there is still enough antioxidant potencyleft in the polymeric material both at the surface and in the bulk so asnot to compromise oxidation stability of the polymeric material in thelong-term. For instance the polymeric material with spatially varyingantioxidant concentration is irradiated at an elevated temperature aboveroom temperature, preferably at about 40° C., at above 40° C., at 75°C., at above 75° C., at about 100° C., at about 110° C., or at about120° C.

Another advantage of this approach where cross-linking is constrained toa thin surface layer is that the overall bulk mechanical properties ofthe polymeric article are not altered compared to unirradiated UHMWPE asthey would be if the cross-links were uniformly distributed throughoutthe entire article.

Another added benefit of this invention is that the α-tocopherol dopingcan be carried out at elevated temperatures to shorten the diffusiontime.

All of the embodiments are described with α-tocopherol as theantioxidant but any other antioxidant or mixtures of antioxidants alsocan be used.

According to one embodiment, the polymeric material is an article havinga shape of an implant, a preform that can be machined to an implantshape, or any other shape.

In one embodiment, the polymeric article is prepared withα-tocopherol-rich and α-tocopherol-poor regions where theα-tocopherol-poor regions are located at one or more of the surface(exterior regions) and the α-tocopherol-rich regions are in the bulk(generally the interior regions).

An advantage of starting with α-tocopherol-rich and α-tocopherol-poorregions in the polymeric article is that the radiation cross-linkingwill primarily be limited to the α-tocopherol-poor regions (in mostembodiments the articular surfaces) and therefore the reduction in themechanical properties of the implant due to cross-linking will beminimized.

In another embodiment, the consolidated polymeric material is fabricatedthrough direct compression molding (DCM). The DCM mold is filled with acombination of polyethylene powder containing α-tocopherol and withvirgin polyethylene powder, that is without α-tocopherol (see schematicdiagram in FIG. 1). The mold is then heated and pressurized to completethe DCM process. The consolidated polymeric material thus formedconsists of α-tocopherol rich and α-tocopherol-poor regions. Theconcentration of α-tocopherol in the initial α-tocopherol-containingpowder may be sufficiently high to retain its antioxidant efficiencythroughout the DCM process, and any subsequent irradiation and cleaningsteps. This concentration is between about 0.0005 wt % and about 20 wt %or higher, preferably between 0.005 wt % and 5.0 wt %, preferably about0.5 wt % or 1.0 wt %, preferably about 0.3 wt %, or preferably about 0.2wt % or 0.1 wt %. The DCM mold is filled with either or both of thepowders to tailor the spatial distribution of the α-tocopherol-rich andα-tocopherol-poor regions in the consolidated polymeric article Oneissue is the diffusion of α-tocopherol from the blended powder regionsto the virgin powder regions, especially during consolidation where hightemperatures and durations are typical. Any such diffusion would reducethe efficiency of subsequent cross-linking in the affected virgin powderregions. One can control the diffusion process by precisely tailoringthe spatial distribution of the α-tocopherol rich and α-tocopherol-poorregions, by optimizing the content of α-tocopherol in the blendedregions, by reducing the temperature of consolidation, and/or reducingthe time of consolidation.

In another embodiment, the consolidated polymeric material is fabricatedthrough direct compression molding (DCM). The DCM mold is filled with acombination of polyethylene powder containing a high concentration ofα-tocopherol and with polyethylene powder containing a low concentrationof α-tocopherol (see schematic diagram in FIG. 32). The mold is thenheated and pressurized to complete the DCM process. The consolidatedpolymeric material thus formed consists of α-tocopherol rich andα-tocopherol-poor regions. The concentration of α-tocopherol in theinitial high α-tocopherol-containing powder region may be sufficientlyhigh to retain its antioxidant efficiency throughout the DCM process,and any subsequent irradiation and cleaning steps. It can also be highenough to decrease crosslinking density after radiation compared toconsolidated stock made from virgin UHMWPE. This concentration isbetween about 0.0005 wt % and about 20 wt % or higher, preferablybetween 0.005 wt % and 5.0 wt %, preferably about 0.5 wt % or 1.0 wt %,preferably about 0.3 wt %, or preferably about 0.2 wt % or 0.1 wt %. Theconcentration of α-tocopherol in the initial low α-tocopherol-containingpowder region may be sufficiently high to retain its antioxidantefficiency throughout the DCM process, and any subsequent irradiationand cleaning steps. It can also be low enough not to change crosslinkingdensity after radiation compared to consolidated stock made from virginUHMWPE. This concentration is between about 0.0005 wt % and about 20 wt% or higher, preferably between 0.005 wt % and 5.0 wt %, preferablyabout 0.5 wt % or 1.0 wt %, preferably about 0.3 wt %, or preferablyabout 0.2 wt % or 0.1 wt %. The DCM mold is filled with either or bothof the powders to tailor the spatial distribution of theα-tocopherol-rich and α-tocopherol-poor regions in the consolidatedpolymeric article. One issue is the diffusion of α-tocopherol from theblended powder regions containing high concentration of α-tocopherol tothe blended powder regions containing low concentration of α-tocopherol,especially during consolidation where high temperatures and durationsare typical. One can control the diffusion process by preciselytailoring the spatial distribution of the α-tocopherol-rich andα-tocopherol-poor regions, by optimizing the content of α-tocopherol inthe blended regions, by reducing the temperature of consolidation,and/or reducing the time of consolidation or placing diffusion barrierin between the two regions such as a previously molded piece of UHMWPE,with or without antioxidant.

In some embodiments the α-tocopherol rich region is confined to the coreof the polymeric article and the virgin polymer is confined to the outershell whereby the thickness of the α-tocopherol-poor region is betweenabout 0.01 mm and 20 mm, more preferably between about 1 mm and 5 mm, ormore preferably about 3 mm.

In some embodiments the outer layer is limited to only one or more facesof the polymeric article. For example a polymeric article is madethrough DCM process by compression molding two layers of polyethylenepowder, one containing 0.3 or 0.5 wt % α-tocopherol and one virgin withno α-tocopherol or containing a low concentration of α-tocopherol suchas 0.02 or 0.05 wt %. The order in which the two powders are placed intothe mold determines which faces of the polymeric article areα-tocopherol-poor and the thickness of the α-tocopherol-poor region isdetermined by the amount of virgin powder used. Alternatively, thethickness of the α-tocopherol-poor region is determined afterconsolidation or after any of the subsequent steps by machining awaysample from the surface. This polymeric article is subsequentlyirradiated, doped with α-tocopherol, homogenized, machined on one ormore of the faces to shape a polymeric implant, packaged and sterilized.

In some embodiments, the α-tocopherol-rich region is molded from a blendof α-tocopherol-containing powder and virgin polyethylene powder or aα-tocopherol-containing powder with a low concentration of α-tocopherol.

In some embodiments, the powder containing α-tocopherol and the virginpolyethylene powder or α-tocopherol-containing powder with a lowconcentration of α-tocopherol are dry-mixed prior to molding, therebycreating a distribution of α-tocopherol-rich and α-tocopherol-poorregions throughout the polyethylene article.

In some embodiments, the virgin polyethylene region is confined to thearticular bearing surface of the implant.

In some embodiments, the powder containing α-tocopherol undergoespartial or complete consolidation prior to the DCM process (see FIG. 1).This preformed piece of α-tocopherol-containing polyethylene allows moreprecise control over the spatial distribution of α-tocopherol in thefinished part. For example, the partially or completely consolidatedpowder is placed in a mold surrounded by virgin powder orα-tocopherol-containing powder with a low concentration of α-tocopheroland further consolidated, creating a polyethylene article with anα-tocopherol-poor region on the outer shell and α-tocopherol-rich regionin the bulk of the polyethylene article.

In another embodiment a polyethylene component is fabricated through DCMas described above with spatially-controlled α-tocopherol-rich andα-tocopherol-poor regions. This component is subsequently treated bye-beam irradiation. E-beam irradiation is known to have a gradientcross-linking effect in the direction of the irradiation, but this isnot always optimized in components which have curved surfaces, such asacetabular cups, where the cross-linking will be different at differentpoints on the articulating surface. The spatial distribution ofα-tocopherol-rich regions is used in conjunction with e-beam irradiationto create uniform surface cross-linking which gradually decreases tominimal cross-linking in the bulk. After irradiation, the polyethylenecomponent is doped with α-tocopherol. This component is cross-linked andstabilized at the surface and transitions to the uncross-linked andstabilized material with increasing depth from the surface.

In some embodiments the vitamin-E/polyethylene blended powder mixturehas a very high vitamin-E concentration such that when this powdermixture is consolidated with neat powder there is a steep gradient ofvitamin-E across the interface. The consolidated piece is thenirradiated to cross-link the polymer preferably in the neatα-tocopherol-poor region. Subsequently, the piece is heated to drivediffusion of α-tocopherol from the α-tocopherol-rich bulk region to theα-tocopherol-poor surface region.

In some embodiments, a vitamin-E-polyethylene (for example, UHMWPE)blend and virgin polyethylene resin powder or α-tocopherol-containingpowder with a low concentration of α-tocopherol are molded together tocreate an interface. The quantities of the high concentration blendand/or the low concentration blend or virgin resins are tailored toobtain a desired α-tocopherol-poor polyethylene thickness.Alternatively, the molded piece/material is machined to obtain thedesired thickness of the virgin polyethylene layer. The machined-moldedpiece/material is irradiated followed by:

Either doping with vitamin E and homogenized below the melting point orabove the melting point of the polyethylene,

or heated above the melt without doping to eliminate the free radicals(for example, for different durations),

or heated above the melt for long enough duration, which will alsodiffuse the bulk vitamin E from the vitamin E-rich blend layer into thevitamin E-poor layer (for example, for different durations, differentblend compositions are used to accelerate the diffusion from the richregion to the poor region),

or high pressure crystallized/annealed, thereby forming a medicalimplant. The medical implant can be used at this stage or can bemachined further to remove any oxidized surface layers to obtain a netshaped implant. The implant also can be packaged and sterilized.

In another embodiment, the antioxidant-doped or -blended polymericmaterial is homogenized at a temperature below or above the meltingpoint of the polymeric material for a desired period of time, forexample, the antioxidant-doped or -blended polymeric material ishomogenized for about an hour to several days to one week or more thanone week at room temperature to about 400° C. Preferably, thehomogenization is carried out above room temperature, preferably atabout 90° C. to about 180° C., more preferably about 100° C. to about137° C., more preferably about 120° C. to about 135° C., most preferablyabout 130° C.

A purpose of homogenization is to make the concentration profile ofα-tocopherol throughout the interior of a consolidated polymericmaterial more spatially uniform. After doping of the polymeric materialis completed, the consolidated polymeric material is removed from thebath of α-tocopherol and wiped thoroughly to remove excess α-tocopherolfrom the surfaces of the polymeric material. The polymeric material iskept in an inert atmosphere (nitrogen, argon, and/or the like) or in airduring the homogenization process. The homogenization also can bepreformed in a chamber with supercritical fluids such as carbon dioxideor the like.

In another embodiment, the DCM process is conducted with a metal piecethat becomes an integral part of the consolidated polyethylene article(see schematic diagram in FIG. 2). For example, a combination ofα-tocopherol-containing polyethylene powder and virgin polyethylenepowder is direct compression molded into a metallic acetabular cup or atibial base plate with a spatially controlled distribution ofα-tocopherol-rich and α-tocopherol-poor regions so that cross-linking ofthe polyethylene during the subsequent irradiation step is not hinderedat the articular surfaces. For example, the porous tibial metal baseplate is placed in the mold, α-tocopherol blended polyethylene powder isadded on top and then virgin polyethylene powder is added last.Following consolidation the article is α-tocopherol-rich near the metalpiece and also in the bulk but the articular surface isα-tocopherol-poor, which allows cross-linking of the surface layerduring subsequent irradiation. Doping of the article with α-tocopherolis carried out after irradiation to stabilize the free radicals near thearticular surface. Prior to the DCM consolidation the pores of the metalpiece can be filled with a waxy substance through half the thickness toachieve polyethylene interlocking through the other unfilled half of themetallic piece. The pore filler is maintained through the irradiationand subsequent α-tocopherol doping steps to prevent infusion ofα-tocopherol in to the pores of the metal. In some embodiments, thearticle is machined after doping to shape an implant.

Elution of vitamin E from irradiated and vitamin E doped/containingUHMWPE parts is observed during shelf storage at 40° C. or storage inwater at 40° C. The latter simulated an in vivo environment andextraction of vitamin E from these parts in this simulated in vivoenvironment raised concerns as to the potential local tissue response tothe exuding vitamin E and also as to the long-term oxidative stabilityof the implant when enough vitamin E is exuded out. Therefore, someexperiments that are devised first also are disclosed herein, todetermine the oxidative stability of irradiated and vitamin Edoped/containing UHMWPE parts after forceful extraction/elution ofvitamin E, for example, by soaking in boiling hexane for 72 hours; andsecond, developed methods to extract vitamin E from the irradiated andvitamin E doped/containing UHMWPE parts to prevent in vivo elution ofthe vitamin E.

The elution of α-tocopherol from an implanted device can potentiallyeffect the surrounding tissues and joint spaces. Therefore, it isbeneficial to extract the excess and elutable α-tocopherol from thesurface region of antioxidant containing polymeric materials prior toplacement and/or implantation to minimize the elution of α-tocopherol invivo. The present invention provides several approaches as to how thiscan be achieved and provides methods of extraction of α-tocopherol fromthe surface region of antioxidant containing polymeric materials. Thepresent invention also provides an example where all of the detectableα-tocopherol is extracted from an irradiated and α-tocopherol dopedUHMWPE, which continued to be stable against oxidation even after theextraction, based on two weeks aging in oxygen at 5 atm at 70° C. (ASTMF2003-02). Therefore, removal of the excess or at least partial removalof the α-tocopherol can be used to minimize the in vivo elution of theα-tocopherol from irradiated and α-tocopherol-doped/containing UHMWPEparts.

In most of the embodiments, α-tocopherol is described as an antioxidant;however, any other antioxidants known in the art or a mixture thereofalso can be used.

In an embodiment, the polymeric material, for example, UHMWPE, is usedas an article having a shape of a medical implant, an implant preformthat can be machined to an implant shape or any other desirable shape.

In an embodiment, the polymeric article is prepared with a gradient ofα-tocopherol concentration (by elution, for example) where the surface(exterior regions) has less α-tocopherol than the bulk (interiorregions).

In an embodiment, consolidated polymeric material with a gradient ofα-tocopherol is prepared by the following method as illustrated inschematically (see FIG. 14): Consolidated polymeric material is formedby consolidating UHMWPE powder-α-tocopherol blend. The consolidation canbe achieved through standard consolidation techniques such as ramextrusion, compression molding, or direct compression molding atelevated temperature and pressure, or other known approaches.Subsequently, the consolidated polyethylene article is extracted toremove the excess α-tocopherol or at least partially the α-tocopherolfrom the surface regions. The extraction can be carried out by placingthe polyethylene in an alcohol, such as isopropyl alcohol (IPA),ethanol, or an aqueous solution of alcohol, in water, in watercontaining a surfactant such as tween-80, in an organic solvent such asxylene, hexane, toluene, or other, or a mixture thereof. The extractionalso can be performed in supercritical fluids, such as water, CO₂,ethane, propane, other gases, or mixtures thereof.

The extraction can be carried out at room temperature or at elevatedtemperatures below or above the melting point of the polymeric material.At temperatures above the boiling point of the solvent or solventmixtures used, pressure can be applied to achieve the desiredtemperature.

In another embodiment, a polyethylene article is doped or doped andhomogenized with α-tocopherol and subsequently subjected to anextraction step to remove the excess α-tocopherol or at least a portionof the α-tocopherol from the surface regions.

Another advantage of starting with a gradient of α-tocopherolconcentration in the polyethylene article is that the radiationcross-linking is primarily occurs in the α-tocopherol deficient regions(in most embodiments the articular surfaces) and therefore, thereduction in the mechanical properties of the implant due tocross-linking is minimized.

In another embodiment, an implant or a preform is made out ofα-tocopherol and UHMWPE powder blend either by machining a largeconsolidate made from the powder blend or by direct compression moldingthe powder blend. The implant or preform is then placed in a solvent orsolvent mixture or in a gas or gas mixture or in a supercritical fluidor fluid mixture to extract the α-tocopherol from near the outsidesurfaces. It is beneficial to have reduced the α-tocopherolconcentration within 1 micrometer of the surface up to severalmillimeters or beyond. The implant or preform is then irradiated. Thesurface (exterior regions), which is depleted of α-tocopherol to acertain extent, will have a higher cross-link density than the bulk(interior regions). Following irradiation, the surface may not haveenough α-tocopherol left because of the surface depletion step isperformed prior to the irradiation. Therefore doping the implant afterirradiation may be necessary to stabilize the free radicals, especiallynear the surface.

In another embodiment, the polyethylene article is fabricated throughdirect compression molding (DCM). The DCM mold is filled withpolyethylene powder containing α-tocopherol. The mold is then heated andpressurized to complete the DCM process. The polyethylene article thusformed consists of α-tocopherol containing regions. The concentration ofα-tocopherol in the α-tocopherol-containing powder may be sufficientlyhigh to retain its antioxidant efficiency throughout the DCM process,and any subsequent irradiation, extraction and cleaning steps. Thisconcentration is between about 0.0005 wt % and about 20 wt % or higher,preferably between 0.005 wt % and 5.0 wt %, preferably about 0.3 wt %,or preferably about 0.5 wt %. The DCM mold is filled with the UHMWPEpowder to blend in α-tocopherol in the consolidated polyethylenearticle.

This polyethylene article is subsequently irradiated, doped withα-tocopherol, homogenized, subjected to an extraction step to remove theexcess α-tocopherol or at least a portion of the α-tocopherol from thesurface region(s), machined on one or more of the faces to shape apolyethylene implant, cleaned, packaged and sterilized.

This polyethylene article is subsequently irradiated, doped withα-tocopherol, homogenized, machined on one or more of the faces to shapea polyethylene implant subjected to an extraction step to remove theexcess α-tocopherol or at least a portion of the α-tocopherol from thesurface region(s), cleaned, packaged and sterilized.

In some embodiments, a vitamin-E-polyethylene (for example, UHMWPE)blend is molded together to create an interface. The machined-moldedpiece/material is then subjected to an extraction step, to remove theexcess α-tocopherol or at least a portion of the α-tocopherol from thesurface regions, and irradiated followed by:

-   -   Either doping with vitamin E and homogenized below the melting        point or above the melting point of the polyethylene,    -   or doping with vitamin E and homogenized below the melting point        or above the melting point of the polyethylene, then subjected        to an extraction step to remove the excess α-tocopherol or at        least a portion of the α-tocopherol from the surface regions,    -   or heated above the melt without doping to eliminate the free        radicals (for example, for different durations),    -   or heated above the melting temperature for long enough duration        to form a homogeneous blend, thereby forming a medical implant.        The medical implant can be used at this stage or can be machined        further to remove any oxidized surface layers to obtain a net        shaped implant. The implant also can be packaged and sterilized.

In another embodiment, the antioxidant-doped or -blended polymericmaterial is homogenized at a temperature below or above the meltingpoint of the polymeric material for a desired period of time, forexample, the antioxidant-doped or -blended polymeric material ishomogenized for about an hour to several days (1 to 28 days), preferablyfor 24 hours. After doping/blending of polyethylene with α-tocopherol,the homogenization step is employed. A purpose of homogenization is tomake the concentration profile of α-tocopherol throughout the interiorof the polyethylene sample more spatially uniform. After doping iscompleted, the polyethylene is removed from the bath of α-tocopherol andwiped thoroughly to remove excess α-tocopherol from the surfaces of thepolyethylene. The polyethylene is then homogenized at a temperaturebetween room temperature and about 400° C. Preferably, thehomogenization is carried out above room temperature, preferably atabout 90° C. to about 180° C., more preferably about 100° C. to about137° C., more preferably about 120° C. to about 135° C., most preferablyabout 130° C. The polyethylene is kept in an inert atmosphere (nitrogen,argon, and/or the like) or in air during the homogenization process. Thehomogenization also can be performed in a chamber with supercriticalfluids such as carbon dioxide or the like.

In another embodiment, there are more than one metal pieces integral tothe polyethylene article.

In another embodiment, one or some or all of the metal pieces integralto the polyethylene article is a porous metal piece that allows bonein-growth when implanted into the human body.

In some embodiments, one or some or all of the metal pieces integral tothe polyethylene article is a non-porous metal piece.

In one embodiment, the consolidated polyethylene article is irradiatedusing ionizing radiation such as gamma, electron-beam, or x-ray to adose level between about 1 and about 10,000 kGy, preferably about 25 toabout 250 kGy, preferably about 50 to about 150 kGy, preferably about 65kGy, preferably about 85 kGy, or preferably about 100 kGy.

In another embodiment, the irradiated polyethylene article is doped withα-tocopherol by placing the article in an α-tocopherol bath at roomtemperature or at an elevated temperature for a given amount of time.

In another embodiment, the doped polyethylene article is heated above orbelow the melting point of the polyethylene.

In another embodiment, the doped polyethylene article is heated above orbelow the melting point of the polyethylene under pressure. Pressure canbe applied in water, any fluid, an inert gas, a non-inert gas, or asupercritical fluid. Pressure also can be applied mechanically.

In one embodiment, the metal mesh of the implant is sealed using asealant to prevent or reduce the infusion of α-tocopherol into the poresof the mesh during the selective doping of the implant. Preferably thesealant is water soluble. But other sealants are also used. The finalcleaning step that the implant is subjected to also removes the sealant.Alternatively, an additional sealant removal step is used. Such sealantsas water, saline, aqueous solutions of water soluble polymers such aspoly-vinyl alcohol, water soluble waxes, plaster of Paris, or others areused. In addition, a photoresist like SU-8, or other, may be curedwithin the pores of the porous metal component. Following processing,the sealant may be removed via an acid etch or a plasma etch.

In another embodiment, the polyethylene-porous metal mono-block is dopedso that the polyethylene is fully immersed in α-tocopherol but theporous metal is either completely above the α-tocopherol surface or onlypartially immersed during doping. This reduces infusion of α-tocopherolinto the pores of the metal mesh.

In yet another embodiment, the doped polyethylene article is machined toform a medical implant. In some embodiments, the machining is carriedout on sides with no metallic piece if at least one is present.

In most embodiments, the medical devices are packaged and sterilized.

In another aspect of the invention, the medical device is cleaned beforepackaging and sterilization.

In other embodiments, the antioxidant, for example, vitamin E,concentration profiles in implant components can be controlled inseveral different ways, following various processing steps in differentorders, for example:

-   -   I. Blending the antioxidant and polyethylene resin, powder, or        flakes, consolidating the blend, machining of implants,        radiation cross-linking (at a temperature above or below the        melting point of the polymeric material), and doping with the        antioxidant;    -   II. Blending the antioxidant and polyethylene resin, powder, or        flakes, consolidating the blend, machining of implants,        radiation cross-linking (at a temperature above or below the        melting point of the polymeric material), doping with the        antioxidant and homogenizing;    -   III. Blending the antioxidant and polyethylene resin, powder, or        flakes, consolidating the blend, machining of implants,        radiation cross-linking (at a temperature above or below the        melting point of the polymeric material), doping with the        antioxidant and homogenizing, extracting/eluting out the excess        antioxidant or at least a portion of the antioxidant;    -   IV. Blending the antioxidant and polyethylene resin, powder, or        flakes, consolidating the blend, machining of preforms,        radiation cross-linking (at a temperature above or below the        melting point of the polymeric material), doping with the        antioxidant, machining of implants;    -   V. Blending the antioxidant and polyethylene resin, powder, or        flakes, consolidating the blend, machining of preforms,        radiation cross-linking (at a temperature above or below the        melting point of the polymeric material), doping with the        antioxidant and homogenizing, machining of implants;    -   VI. Blending the antioxidant and polyethylene resin, powder, or        flakes, consolidating the blend, machining of preforms,        radiation cross-linking (at a temperature above or below the        melting point of the polymeric material), doping with the        antioxidant and homogenizing, machining of implants, extraction        of the antioxidant;    -   VII. Radiation cross-linking of consolidated polymeric material        (at a temperature above or below the melting point of the        polymeric material), machining implant, doping with the        antioxidant, extracting/eluting out the excess antioxidant or at        least a portion of the antioxidant;    -   VIII. Radiation cross-linking of consolidated polymeric material        (at a temperature above or below the melting point of the        polymeric material), machining implants, doping with the        antioxidant and homogenizing, extracting/eluting out the excess        antioxidant or at least a portion of the antioxidant;    -   IX. Radiation cross-linking of consolidated polymeric material        (at a temperature above or below the melting point of the        polymeric material), machining preforms, doping with the        antioxidant, extraction of the antioxidant, machining of        implants;    -   X. Radiation cross-linking of consolidated polymeric material        (at a temperature above or below the melting point of the        polymeric material), machining preforms, doping with the        antioxidant and homogenizing, extracting/eluting out the excess        antioxidant or at least a portion of the antioxidant, machining        of implants;    -   XI. Radiation cross-linking of consolidated polymeric material        (at a temperature above or below the melting point of the        polymeric material), machining preforms, doping with the        antioxidant, machining of implants, extracting/eluting out the        excess antioxidant or at least a portion of the antioxidant;        and/or    -   XII. Radiation cross-linking of consolidated polymeric material        (at a temperature above or below the melting point of the        polymeric material), machining preforms, doping with the        antioxidant and homogenizing, machining of implants,        homogenizing, extracting/eluting out the excess antioxidant or        at least a portion of the antioxidant.

In another embodiment, all of the above processes are further followedby cleaning, packaging and sterilization (gamma irradiation, e-beamirradiation, ethylene oxide or gas plasma sterilization).

According to another embodiment, in all of the above steps, theextraction can be done with a compatible solvent that dissolves theantioxidant. Such solvents include a hydrophobic solvent, such ashexane, heptane, or a longer chain alkane; an alcohol such as ethanol,any member of the propanol or butanol family or a longer chain alcohol;or an aqueous solution in which the antioxidant is soluble. Suchsolvents also can be made by using an emulsifying agent, such as Tween80 or ethanol.

In some embodiments, antioxidant is extracted/eluted from anantioxidant-doped/containing consolidated polymeric material bycontacting the consolidated polymeric material with a solvent in whichthe antioxidant is soluble or at least partially soluble.

High pressure crystallization is generally referred to as all of themethods of allowing the formation of extended chain crystals in thehexagonal phase. This transformation can be used alone or in combinationwith any of the methods described above. A method used for high pressurecrystallization is by heating to a temperature above the melting pointof the polyethylene at ambient pressure, then pressurizing so that thesample is in the melt during the pressurization until the conditions aremet for the melt-to-hexagonal transformation to occur. Also, stepwiseheating and pressurization can be performed such that the sample is notalways in the melt until close to the hexagonal phase. The sampleheating and pressurization can be done in a variety of manners such thatwhen the hexagonal phase transformation occurs, the UHMWPE does not havea substantial amount of crystals and is considered in the melt phase.

Once the conditions are met for the hexagonal phase to be achieved andthe extended chain crystals are formed, the sample cannot be allowed tocompletely melt because the desired crystalline structure would be lost.Therefore, any cooling and depressurization scheme allowing the sampleto stay in the hexagonal or orthorhombic regions could be used. Forexample, a sample high pressure crystallized at about 200° C. and 380MPa (55,000 psi) can be cooled down to approximately below the meltingpoint of polyethylene at room temperature (about 135-140° C.), then thepressure can be released. Also, a stepwise cooling and depressurizationmethod can be used as long as the sample does not melt substantially.

The ratio of folded to extended crystals may be dependent on the timespent in the hexagonal phase and whether or not the sample has melted.If a sample is fully crystallized in the hexagonal phase, is cooled downand/or depressurized to a pressure such that it encounters the meltphase partially or completely, and solely decreasing the temperature atthe new pressure would not cause the sample to be in the hexagonalphase, then some or all of the crystals would be converted to foldedchain crystals when the sample is further cooled down and depressurized.

1. High pressure crystallization of polyethylene can be achieved throughthe melt phase (high pressure crystallization) or through the solidphase (high pressure annealing):

-   -   A. High pressure crystallization (Route I): Heat to the desired        temperature, for example, above the melt (for example, about        140° C., about 160° C., about 180° C., about 200° C., about 250°        C., or about 300° C.); then pressurize; then hold pressure at        about the same pressure, for one minute to a day or more,        preferably about 0.5 hours to 12 hours, more preferably 1 to 6        hours; then release the pressure (pressure has to be released        after cooling down to below the melting point of the polymeric        material to avoid melting of the crystals achieved under high        pressure).    -   B. High pressure annealing (Route II): Pressurize to the desired        pressure; then heat to the desired temperature, for example,        below the melt of pressurized polyethylene (for example, about        150° C., about 160° C., about 180° C., about 195° C., about 225°        C., about 300° C., and about 320° C.); then hold pressure at        about the same pressure, for one minute to a day or more,        preferably about 0.5 hours to 12 hours, more preferably 1 to 6        hours; then cool to room temperature; then release the pressure        (pressure has to be released after cooling down to below the        melting point of the polymeric material to avoid melting of the        crystals achieved under high pressure).

Methods and Sequence of Irradiation:

The selective, controlled manipulation of polymers and polymer alloysusing radiation chemistry can, in another aspect, be achieved by theselection of the method by which the polymer is irradiated. Theparticular method of irradiation employed, either alone or incombination with other aspects of the invention, such as the polymer orpolymer alloy chosen, contribute to the overall properties of theirradiated polymer.

Gamma irradiation or electron radiation may be used. In general, gammairradiation results in a higher radiation penetration depth thanelectron irradiation. Gamma irradiation, however, generally provides lowradiation dose rate and requires a longer duration of time, which canresult in more in-depth and extensive oxidation, particularly if thegamma irradiation is carried out in air. Oxidation can be reduced orprevented by carrying out the gamma irradiation in an inert gas, such asnitrogen, argon, or helium, or under vacuum. Electron irradiation, ingeneral, results in more limited dose penetration depth, but requiresless time and, therefore, reduces the risk of extensive oxidation if theirradiation is carried out in air. In addition if the desired doselevels are high, for instance 20 Mrad, the irradiation with gamma maytake place over one day, leading to impractical production times. On theother hand, the dose rate of the electron beam can be adjusted byvarying the irradiation parameters, such as conveyor speed, scan width,and/or beam power. With the appropriate parameters, a 20 Mradmelt-irradiation can be completed in for instance less than 10 minutes.The penetration of the electron beam depends on the beam energy measuredby million electron-volts (MeV). Most polymers exhibit a density ofabout 1 g/cm³, which leads to the penetration of about 1 cm with a beamenergy of 2-3 MeV and about 4 cm with a beam energy of 10 MeV. Ifelectron irradiation is preferred, the desired depth of penetration canbe adjusted based on the beam energy. Accordingly, gamma irradiation orelectron irradiation may be used based upon the depth of penetrationpreferred, time limitations and tolerable oxidation levels.

According to certain embodiments, the cross-linked polymeric materialcan have a melt history, meaning that the polymeric material is meltedconcurrently with or subsequent to irradiation for cross-linking.According to other embodiments, the cross-linked polymeric material hasno such melt history.

Various irradiation methods including IMS, CIR, CISM, WIR, and WIAM aredefined and described in greater detail below for cross-linked polymericmaterials with a melt history, that is irradiated with concurrent orsubsequent melting:

(i) Irradiation in the Molten State (IMS):

Melt-irradiation (MIR), or irradiation in the molten state (“IMS”), isdescribed in detail in U.S. Pat. No. 5,879,400. In the IMS process, thepolymer to be irradiated is heated to at or above its melting point.Then, the polymer is irradiated. Following irradiation, the polymer iscooled.

Prior to irradiation, the polymer is heated to at or above its meltingtemperature and maintained at this temperature for a time sufficient toallow the polymer chains to achieve an entangled state. A sufficienttime period may range, for example, from about 5 minutes to about 3hours. For UHMWPE, the polymer may be heated to a temperature betweenabout 145° C. and about 230° C., preferably about 150° C. to about 200°C.

Gamma irradiation or electron radiation may be used. In general, gammairradiation results in a higher radiation penetration depth thanelectron irradiation. Gamma irradiation, however, generally provides lowradiation dose rate and requires a longer duration of time, which canresult in more in-depth oxidation, particularly if the gamma irradiationis carried out in air. Oxidation can be reduced or prevented by carryingout the gamma irradiation in an inert gas, such as nitrogen, argon, orhelium, or under vacuum. Electron irradiation, in general, results inmore limited dose penetration depth, but requires less time and,therefore, reduces the risk of extensive oxidation if the irradiation iscarried out in air. In addition if the desired dose levels are high, forinstance 20 Mrad, the irradiation with gamma may take place over oneday, leading to impractical production times. On the other hand, thedose rate of the electron beam can be adjusted by varying theirradiation parameters, such as conveyor speed, scan width, and/or beampower. With the appropriate parameters, a 20 Mrad melt-irradiation canbe completed in for instance less than 10 minutes. The penetration ofthe electron beam depends on the beam energy measured by millionelectron-volts (MeV). Most polymers exhibit a density of about 1g/cm.sup.3, which leads to the penetration of about 1 cm with a beamenergy of 2-3 MeV and about 4 cm with a beam energy of 10 MeV. Thepenetration of e-beam is known to increase slightly with increasedirradiation temperatures. If electron irradiation is preferred, thedesired depth of penetration can be adjusted based on the beam energy.Accordingly, gamma irradiation or electron irradiation may be used basedupon the depth of penetration preferred, time limitations and tolerableoxidation levels.

The temperature of melt-irradiation for a given polymer depends on theDSC (measured at a heating rate of 10° C./min during the first heatingcycle) peak melting temperature (“PMT”) for that polymer. In general,the irradiation temperature in the IMS process is at least about 2° C.higher than the PMT, more preferably between about 2° C. and about 20°C. higher than the PMT, and most preferably between about 5° C. andabout 10° C. higher than the PMT.

The total dose of irradiation also may be selected as a parameter incontrolling the properties of the irradiated polymer. In particular, thedose of irradiation can be varied to control the degree of cross-linkingand crystallinity in the irradiated polymer. The total dose may rangefrom about 0.1 Mrad to as high as the irradiation level where thechanges in the polymer characteristics induced by the irradiation reacha saturation point. For instance the high end of the dose range could be20 Mrad for the melt-irradiation of UHMWPE, above which dose level thecross-link density and crystallinity are not appreciably affected withany additional dose. The preferred dose level depends on the desiredproperties that will be achieved following irradiation. Additionally,the level of crystallinity in polyethylene is a strong function ofradiation dose level. See Dijkstra et al., Polymer 30: 866-73 (1989).For instance with IMS irradiation, a dose level of about 20 Mrad woulddecrease the crystallinity level of UHMWPE from about 55% to about 30%.This decrease in crystallinity may be desirable in that it also leads toa decrease in the elastic modulus of the polymer and consequently adecrease in the contact stress when a medical prosthesis made out of theIMS-treated UHMWPE gets in contact with another surface during in vivouse. Lower contact stresses are preferred to avoid failure of thepolymer through, for instance, subsurface cracking, delamination,fatigue, etc. The increase in the cross-link density is also desirablein that it leads to an increase in the wear resistance of the polymer,which in turn reduces the wear of the medical prostheses made out of thecross-linked polymer and substantially reduces the amount of wear debrisformed in vivo during articulation against a counterface. In general,the melt-irradiation and subsequent cooling will lead to a decrease inthe crystallinity of the irradiated polymer.

Exemplary ranges of acceptable total dosages are disclosed in greaterdetail in U.S. Pat. No. 5,879,400 and International Application WO97/29793. For example, preferably a total dose of about or greater than1 MRad is used. More preferably, a total dose of greater than about 20Mrad is used.

In electron beam IMS, the energy deposited by the electrons is convertedto heat. This primarily depends on how well the sample is thermallyinsulated during the irradiation. With good thermal insulation, most ofthe heat generated is not lost to the surroundings and leads to theadiabatic heating of the polymer to a higher temperature than theirradiation temperature. The heating could also be induced by using ahigh enough dose rate to minimize the heat loss to the surroundings. Insome circumstance, heating may be detrimental to the sample that isbeing irradiated. Gaseous by-products, such as hydrogen gas when PE isirradiated, are formed during the irradiation. During irradiation, ifthe heating is rapid and high enough to cause rapid expansion of thegaseous by-products, and thereby not allowing them to diffuse out of thepolymer, the polymer may cavitate. The cavitation is not desirable inthat it leads to the formation of defects (such as air pockets, cracks)in the structure that could in turn adversely affect the mechanicalproperties of the polymer and in vivo performance of the device madethereof.

The temperature rise depends on the dose level, level of insulation,and/or dose rate. The dose level used in the irradiation stage isdetermined based on the desired properties. In general, the thermalinsulation is used to avoid cooling of the polymer and maintaining thetemperature of the polymer at the desired irradiation temperature.Therefore, the temperature rise can be controlled by determining anupper dose rate for the irradiation. For instance for the IMS of UHMWPEthe dose rate should be less than about 5 Mrad/pass (only applicable forthe e-beam and not gamma as gamma is inherently a low dose rateprocess). These considerations for optimization for a given polymer of agiven size are readily determined by the person of skill in view of theteachings contained herein.

In embodiments of the present invention in which electron radiation isutilized, the energy of the electrons can be varied to alter the depthof penetration of the electrons, thereby controlling the degree ofcross-linking and crystallinity following irradiation. The range ofsuitable electron energies is disclosed in greater detail inInternational Application WO 97/29793. In one embodiment, the energy isabout 0.5 MeV to about 12 MeV. In another embodiment the energy is about1 MeV to 10 MeV. In another embodiment, the energy is about 10 MeV.

(ii) Cold Irradiation (CIR):

Cold irradiation is described in detail in WO 97/29793. In the coldirradiation process, a polymer is provided at room temperature or belowroom temperature. Preferably, the temperature of the polymer is about20° C. Then, the polymer is irradiated. In one embodiment of coldirradiation, the polymer may be irradiated at a high enough total doseand/or at a fast enough dose rate to generate enough heat in the polymerto result in at least a partial melting of the crystals of the polymer.

Gamma irradiation or electron radiation may be used. In general, gammairradiation results in a higher dose penetration depth than electronirradiation. Gamma irradiation, however, generally requires a longerduration of time, which can result in more in-depth oxidation,particularly if the gamma irradiation is carried out in air. Oxidationcan be reduced or prevented by carrying out the gamma irradiation in aninert gas, such as nitrogen, argon, or helium, or under vacuum. Electronirradiation, in general, results in more limited dose penetrationdepths, but requires less time and, therefore, reduces the risk ofextensive oxidation. Accordingly, gamma irradiation or electronirradiation may be used based upon the depth of penetration preferred,time limitations and tolerable oxidation levels.

The total dose of irradiation may be selected as a parameter incontrolling the properties of the irradiated polymer. In particular, thedose of irradiation can be varied to control the degree of cross-linkingand crystallinity in the irradiated polymer. The preferred dose leveldepends on the molecular weight of the polymer and the desiredproperties that will be achieved following irradiation. For instance, toachieve maximum improvement in wear resistance using UHMWPE and the WIAM(warm irradiation and adiabatic melting) or CISM (cold irradiation andsubsequent melting) processes, a radiation dose of about 10 Mrad issuggested. To achieve maximum improvement in wear resistance using LDPEand LLDPE, a dose level greater than about 10 Mrad is suggested. Ingeneral, increasing the dose level with CIR would lead to an increase inwear resistance. If the CIR is carried out without furtherpost-irradiation melting, the crystallinity and elastic modulus of thepolymer would increase. Following melting, however, these would decreaseto values lower than those prior to irradiation.

Exemplary ranges of acceptable total dosages are disclosed in greaterdetail in International Application WO 97/29793. In the embodimentsbelow, UHMWPE is used as the starting polymer. In one embodiment, thetotal dose is about 0.5 MRad to about 1,000 Mrad. In another embodiment,the total dose is about 1 MRad to about 100 MRad. In yet anotherembodiment, the total dose is about 4 MRad to about 30 MRad. In stillother embodiments, the total dose is about 20 MRad or about 15 MRad.

If electron radiation is utilized, the energy of the electrons also is aparameter that can be varied to tailor the properties of the irradiatedpolymer. In particular, differing electron energies will result indifferent depths of penetration of the electrons into the polymer. Thepractical electron energies range from about 0.1 MeV to 16 MeV givingapproximate iso-dose penetration levels of 0.5 mm to 8 cm, respectively.A preferred electron energy for maximum penetration is about 10 MeV,which is commercially available through vendors such as Studer (Daniken,Switzerland) or E-Beam Services (New Jersey, USA). The lower electronenergies may be preferred for embodiments where a surface layer of thepolymer is preferentially cross-linked with gradient in cross-linkdensity as a function of distance away from the surface.

(iii) Warm Irradiation (WIR):

Warm irradiation is described in detail in WO 97/29793. In the warmirradiation process, a polymer is provided at a temperature above roomtemperature and below the melting temperature of the polymer. Then, thepolymer is irradiated. In one embodiment of warm irradiation, which hasbeen termed “warm irradiation adiabatic melting” or “WIAM.” In atheoretical sense, adiabatic heating means an absence of heat transferto the surroundings. In a practical sense, such heating can be achievedby the combination of insulation, irradiation dose rates and irradiationtime periods, as disclosed herein and in the documents cited herein.However, there are situations where irradiation causes heating, butthere is still a loss of energy to the surroundings. Also, not all warmirradiation refers to an adiabatic heating. Warm irradiation also canhave non-adiabatic or partially (such as about 10-75% of the heatgenerated is lost to the surroundings) adiabatic heating. In allembodiments of Wilt, the polymer may be irradiated at a high enoughtotal dose and/or a high enough dose rate to generate enough heat in thepolymer to result in at least a partial melting of the crystals of thepolymer.

The polymer may be provided at any temperature below its melting pointbut preferably above room temperature. The temperature selection dependson the specific heat and the enthalpy of melting of the polymer and thetotal dose level that will be used. The equation provided inInternational Application WO 97/29793 may be used to calculate thepreferred temperature range with the criterion that the finaltemperature of polymer maybe below or above the melting point.Preheating of the polymer to the desired temperature, for example, about50° C., about 60° C., about 70° C., about 80° C., about 85° C., about90° C., about 95° C., about 105° C., about 110° C., about 115° C., orabout 125° C., may be done in an inert or non-inert environment.

Exemplary ranges of acceptable total dosages are disclosed in greaterdetail in international Application WO 97/29793. In one embodiment, theUHMWPE is preheated to about room temperature (about 25° C.) to about135° C. In one embodiment of WIAM, the UHMWPE is preheated to about 100°C. to just below the melting temperature of the polymer. In anotherembodiment of WIAM, the UHMWPE is preheated to a temperature of about100° C. to about 135° C. In yet other embodiments of WIAM, the polymeris preheated to about 120° C. or about 130° C.

In general terms, the pre-irradiation heating temperature of the polymercan be adjusted based on the peak melting temperature (PMT) measure onthe DSC at a heating rate of 10° C./min during the first heat. In oneembodiment the polymer is heated to about 20° C. to about PMT. Inanother embodiment, the polymer is preheated to about 90° C. in anotherembodiment, the polymer is heated to about 100° C. In anotherembodiment, the polymer is preheated to about 30° C. below PMT and 2° C.below PMT. In another embodiment, the polymer is preheated to about 12°C. below PMT.

In the WIAM embodiment of WIR, the temperature of the polymer followingirradiation is at or above the melting temperature of the polymer.Exemplary ranges of acceptable temperatures following irradiation aredisclosed in greater detail in International Application WO 97/29793. Inone embodiment, the temperature following irradiation is about roomtemperature to PMT, or about 40° C. to PMT, or about 100° C. to PMT, orabout 110° C. to PMT, or about 120° C. to PMT, or about PMT to about200° C. In another embodiment, the temperature following irradiation isabout 145° C. to about 190° C. In yet another embodiment, thetemperature following irradiation is about 145° C. to about 190° C. Instill another embodiment, the temperature following irradiation is about150° C.

In WIR, gamma irradiation or electron radiation may be used. In general,gamma irradiation results in a higher dose penetration depth thanelectron irradiation. Gamma irradiation, however, generally requires alonger duration of time, which can result in more in-depth oxidation,particularly if the gamma irradiation is carried out in air. Oxidationcan be reduced or prevented by carrying out the gamma irradiation in aninert gas, such as nitrogen, argon, or helium, or under vacuum. Electronirradiation, in general, results in more limited dose penetrationdepths, but requires less time and, therefore, reduces the risk ofextensive oxidation. Accordingly, gamma irradiation or electronirradiation may be used based upon the depth of penetration preferred,time limitations and tolerable oxidation levels. In the WIAM embodimentof WIR, electron radiation is used.

The total dose of irradiation may also be selected as a parameter incontrolling the properties of the irradiated polymer. In particular, thedose of irradiation can be varied to control the degree of cross-linkingand crystallinity in the irradiated polymer. Exemplary ranges ofacceptable total dosages are disclosed in greater detail inInternational Application WO 97/29793.

The dose rate of irradiation also may be varied to achieve a desiredresult. The dose rate is a prominent variable in the WIAM process. Inthe case of WIAM irradiation of UHMWPE, higher dose rates would providethe least amount of reduction in toughness and elongation at break. Thepreferred dose rate of irradiation would be to administer the totaldesired dose level in one pass under the electron-beam. One also candeliver the total dose level with multiple passes under the beam,delivering a (equal or unequal) portion of the total dose at each time.This would lead to a lower effective dose rate.

Ranges of acceptable dose rates are exemplified in greater detail inInternational Application WO 97/29793. In general, the dose rates willvary between 0.5 Mrad/pass and 50 Mrad/pass. The upper limit of the doserate depends on the resistance of the polymer to cavitation/crackinginduced by the irradiation.

If electron radiation is utilized, the energy of the electrons also is aparameter that can be varied to tailor the properties of the irradiatedpolymer. In particular, differing electron energies will result indifferent depths of penetration of the electrons into the polymer. Thepractical electron energies range from about 0.1 MeV to 16 MeV givingapproximate iso-dose penetration levels of 0.5 mm to 8 cm, respectively.The preferred electron energy for maximum penetration is about 10 MeV,which is commercially available through vendors such as Studer (Daniken,Switzerland) or E-Beam Services New Jersey, USA). The lower electronenergies may be preferred for embodiments where a surface layer of thepolymer is preferentially cross-linked with gradient in cross-linkdensity as a function of distance away from the surface.

(iv) Subsequent Melting (SM)—Substantial Elimination of DetectableResidual Free Radicals:

Depending on the polymer or polymer alloy used, and whether the polymerwas irradiated below its melting point, there may be residual freeradicals left in the material following the irradiation process. Apolymer irradiated below its melting point with ionizing radiationcontains cross-links as well as long-lived trapped free radicals. Someof the free radicals generated during irradiation become trapped in thecrystalline regions and/or at crystalline lamellae surfaces leading tooxidation-induced instabilities in the long-term (see Kashiwabara, H. S.Shimada, and Y. Hori, Free Radicals and Cross-linking in IrradiatedPolyethylene, Radiat. Phys. Chem., 1991, 37(1): p. 43-46; Jahan, M. S.and C. Wang, Combined Chemical and Mechanical Effects on Free radicalsin UHMWPE Joints During Implantation, Journal of Biomedical MaterialsResearch, 1991, 25: p. 1005-1017; Sutula, L. C., et al., Impact of gammasterilization on clinical performance of polyethylene in the hip”,Clinical Orthopedic Related Research, 1995, 3129: p. 1681-1689.). Theelimination of these residual, trapped free radicals through heating canbe, therefore, desirable in precluding long-term oxidative instabilityof the polymer. Iahan M. S. and C. Wang, “Combined chemical andmechanical effects on free radicals in UHMWPE joints duringimplantation”, Journal of Biomedical Materials Research, 1991, 25: p.1005-1017; Sutula, L. C., et al., “Impact of gamma sterilization onclinical performance of polyethylene in the hip”, Clinical OrthopedicRelated Research, 1995, 319: p. 28-4.

Residual free radicals may be reduced by heating the polymer above themelting point of the polymer used. The heating allows the residual freeradicals to recombine with each other. If for a given system the preformdoes not have substantially any detectable residual free radicalsfollowing irradiation, then a later heating step may be omitted. Also,if for a given system the concentration of the residual free radicals islow enough to not lead to degradation of device performance, the heatingstep may be omitted. In some of the lower molecular weight and lowerdensity polyethylenes, the residual free radicals may recombine witheach other even at room temperature over short periods of time, forexample, few hours to few days, to few months. In such cases, thesubsequent heating may be omitted if the increased crystallinity andmodulus resulting from the irradiation is preferred. Otherwise, thesubsequent heating may be carried out to decrease the crystallinity andmodulus. In the case where the heating is omitted, the irradiatedpreform can be directly machined into the final medical device. Thesubsequent heating is also omitted if the polymer contains sufficientantioxidant to prevent oxidation in the long-term.

The reduction of free radicals to the point where there aresubstantially no detectable free radicals can be achieved by heating thepolymer to above the melting point. The heating provides the moleculeswith sufficient mobility so as to eliminate the constraints derived fromthe crystals of the polymer, thereby allowing essentially all of theresidual free radicals to recombine. Preferably, the polymer is heatedto a temperature between the peak melting temperature (PMT) anddegradation temperature (T_(d)) of the polymer, more preferably betweenabout 3° C. above PMT and T_(d), more preferably between about 10° C.above PMT and 50° C. above PMT, more preferably between about 10° C. and12° C. above PMT and most preferably about 15° C. above PMT.

Preferably, for UHMWPE the polymer is heated to a temperature of about137° C. to about 300° C., more preferably about 140° C. to about 300°C., more preferably yet about 140° C. to about 190° C., more preferablyyet about 145° C. to about 300° C., more preferably yet about 145° C. toabout 190° C., more preferably yet about 145° C. to about 190° C., andmost preferably about 150° C. Preferably, the temperature in the heatingstep is maintained for about 0.5 minutes to about 24 hours, morepreferably about 1 hour to about 3 hours, and most preferably about 2hours. The heating can be carried out, for example, in air, in an inertgas, e.g., nitrogen, argon or helium, in a sensitizing atmosphere, forexample, acetylene, or in a vacuum. It is preferred that for the longerheating times, that the heating be carried out in an inert gas or undervacuum to avoid in-depth oxidation.

In certain embodiments, there may be an acceptable level of residualfree radicals in which case, the post-irradiation annealing also can becarried out below the melting point of the polymer, the effects of suchfree radicals can be minimized or eliminated by an antioxidant.

(v) Sequential Irradiation:

The polymer is irradiated with either gamma or e-beam radiation in asequential manner. With e-beam the irradiation is carried out withmultiple passes under the beam and with gamma radiation the irradiationis carried out in multiple passes through the gamma source. Optionally,the polymer is thermally treated in between each or some of theirradiation passes. The thermal treatment can be heating below themelting point or at the melting point of the polymer. The irradiation atany of the steps can be warm irradiation, cold irradiation, or meltirradiation, as described above. For example the polymer is irradiatedwith 30 kGy at each step of the cross-linking and it is first heated toabout 120° C. and then annealed at about 120° C. for about 5 hours aftereach irradiation cycle.

(vi) Blending and Doping:

As stated above, the cross-liked polymeric material can optionally havea melt history, meaning it is melted concurrent with or subsequent toirradiation. The polymeric material can be blended with an antioxidantprior to consolidation and irradiation. Also, the consolidated polymericmaterial can be doped with an antioxidant prior to or after irradiation,and optionally can have been melted concurrent with or subsequent toirradiation. Furthermore, a polymeric material can both be blended withan antioxidant prior to consolidation and doped with an antioxidantafter consolidation (before or after irradiation and optional melting).The polymeric material can be subjected to extraction at different timesduring the process, and can be extracted multiple times as well.

DEFINITIONS

“Antioxidant” refers to what is known in the art as (see, for example,WO 01/80778, U.S. Pat. No. 6,448,315). Alpha- and delta-tocopherol;propyl, octyl, or dedocyl gallates; lactic, citric, ascorbic, tartaricacids, and organic acids, and their salts; orthophosphates, tocopherolacetate. Vitamin E is a preferred antioxidant.

“High-pressure crystallization” refers to a method of making highpressure crystallized polyethylene, according to the invention, asdescribed herein.

“High-pressure annealing” refers to a method of making high pressurecrystallized polyethylene, according to the invention, as describedherein.

The phrase “spatially controlled antioxidant distribution” refers todistribution of antioxidant in a controlled manner, such as a desiredamount of an antioxidant or a mixture of antioxidants is(are) diffusedin or blended in a polymeric material, in order to have a gradient ofantioxidant distribution. A spatial distribution of the antioxidantallows formation of regions within a polymeric material having someregions rich and other regions poor in antioxidant content, which alsocan be termed as a medical implant or preform containing the spatiallycontrolled antioxidant distribution.

“Supercritical fluid” refers to what is known in the art, for example,supercritical propane, acetylene, carbon dioxide (CO₂). In thisconnection the critical temperature is that temperature above which agas cannot be liquefied by pressure alone. The pressure under which asubstance may exist as a gas in equilibrium with the liquid at thecritical temperature is the critical pressure. Supercritical fluidcondition generally means that the fluid is subjected to such atemperature and such a pressure that a supercritical fluid and thereby asupercritical fluid mixture is obtained, the temperature being above thesupercritical temperature, which for CO₂ is 31.3° C., and the pressurebeing above the supercritical pressure, which for CO₂ is 73.8 bar. Morespecifically, supercritical condition refers to a condition of amixture, for example, UHMWPE with an antioxidant, at an elevatedtemperature and pressure, when a supercritical fluid mixture is formed;and then evaporate CO₂ from the mixture, UHMWPE doped with anantioxidant is obtained (see, for example, U.S. Pat. No. 6,448,315 andWO 02/26464)

The term “compression molding” as referred herein related generally towhat is known in the art and specifically relates to high temperaturemolding polymeric material wherein polymeric material is in any physicalstate, including powder form, is compressed into a slab form or mold ofa medical implant, for example, a tibial insert, an acetabular liner, aglenoid liner, a patella, or an unicompartmental insert, aninterpositional device for any joint can be machined.

The term “direct compression molding” (DCM) as referred herein relatedgenerally to what is known in the art and specifically relates tomolding applicable in polyethylene-based devices, for example, medicalimplants wherein polyethylene in any physical state, including powderform, is compressed to solid support, for example, a metallic back,metallic mesh, or metal surface containing grooves, undercuts, orcutouts. The compression molding also includes high temperaturecompression molding of polyethylene at various states, including resinpowder, flakes and particles, to make a component of a medical implant,for example, a tibial insert, an acetabular liner, a glenoid liner, apatella, an interpositional device for any joint or an unicompartmentalinsert.

The term “mechanically interlocked” refers generally to interlocking ofpolyethylene and the counterface, that are produced by various methods,including compression molding, heat and irradiation, thereby forming aninterlocking interface, resulting into a ‘shape memory’ of theinterlocked polyethylene. Components of a device having such aninterlocking interface can be referred to as a “hybrid material”.Medical implants having such a hybrid material contain a substantiallysterile interface.

The term “substantially sterile” refers to a condition of an object, forexample, an interface or a hybrid material or a medical implantcontaining interface(s), wherein the interface is sufficiently sterileto be medically acceptable, i.e., will not cause an infection or requirerevision surgery.

“Metallic mesh” refers to a porous metallic surface of various poresizes, for example, 0.1-3 mm. The porous surface can be obtained throughseveral different methods, for example, sintering of metallic powderwith a binder that is subsequently removed to leave behind a poroussurface; sintering of short metallic fibers of diameter 0.1-3 mm; orsintering of different size metallic meshes on top of each other toprovide an open continuous pore structure.

“Bone cement” refers to what is known in the art as an adhesive used inbonding medical devices to bone. Typically, bone cement is made out ofpolymethylmethacrylate (PMMA).

“High temperature compression molding” refers to the compression moldingof polyethylene in any form, for example, resin powder, flakes orparticles, to impart new geometry under pressure and temperature. Duringthe high temperature (above the melting point of polyethylene)compression molding, polyethylene is heated to above its melting point,pressurized into a mold of desired shape and allowed to cool down underpressure to maintain a desired shape.

“Shape memory” refers to what is known in the art as the property ofpolyethylene, for example, an UHMWPE, that attains a preferred highentropy shape when melted. The preferred high entropy shape is achievedwhen the resin powder is consolidated through compression molding.

The phrase “substantially no detectable residual free radicals” refersto a state of a polyethylene component, wherein enough free radicals areeliminated to avoid oxidative degradation, which can be evaluated byelectron spin resonance (ESR). The phrase “detectable residual freeradicals” refers to the lowest level of free radicals detectable by ESRor more. The lowest level of free radicals detectable withstate-of-the-art instruments is about 10¹⁴ spins/gram and thus the term“detectable” refers to a detection limit of 10¹⁴ spins/gram by ESR.

The terms “about” or “approximately” in the context of numerical valuesand ranges refers to values or ranges that approximate or are close tothe recited values or ranges such that the invention can perform asintended, such as having a desired degree of cross-linking and/or adesired lack or quenching of free radicals, as is apparent to theskilled person from the teachings contained herein. This is due, atleast in part, to the varying properties of polymer compositions. Thusthese terms encompass values beyond those resulting from systematicerror. These terms make explicit what is implicit.

“Polymeric materials” include polyethylene, for example, Ultra-highmolecular weight polyethylene (UHMWPE) refers to linear non-branchedchains of ethylene having molecular weights in excess of about 500,000,preferably above about 1,000,000, and more preferably above about2,000,000. Often the molecular weights can reach about 8,000,000 ormore. By initial average molecular weight is meant the average molecularweight of the UHMWPE starting material, prior to any irradiation. SeeU.S. Pat. No. 5,879,400, PCT/US99/16070, filed on Jul. 16, 1999, andPCT/US97/02220, filed Feb. 11, 1997. The term “polyethylene article” or“polymeric article” generally refers to articles comprising any“polymeric material” disclosed herein.

“Polymeric materials” also include hydrogels, such as poly (vinylalcohol), poly (acrylamide), poly (acrylic acid), poly(ethyl eneglycol), blends thereof, or interpenetrating networks thereof, which canabsorb water such that water constitutes at least 1 to 10,000% of theiroriginal weight, typically 100 wt % of their original weight or 99% orless of their weight after equilibration in water.

“Polymeric material” can be in the form of resin, flakes, powder,consolidated stock and can contain additives such as anti-oxidant(s).The “polymeric material” also can be a blend of one or more of differentresin, flakes or powder containing different concentrations of anadditive such as an antioxidant. The blending of resin, flakes or powdercan be achieved by the blending techniques known in the art. The“polymeric material” also can be a consolidated stock of these blends.

In one embodiment UHMWPE flakes are blended with α-tocopherol;preferably the UHMWPE/α-tocopherol blend is heated to diffuse theα-tocopherol into the flakes. The UHMWPE/α-tocopherol blend is furtherblended with virgin UHMWPE flakes to obtain a blend of UHMWPE flakeswhere some flakes are poor in α-tocopherol and others are rich inα-tocopherol. This blend is then consolidated and irradiated. Duringirradiation the α-tocopherol-poor regions are more highly cross-linkedthan the α-tocopherol-poor regions. Following irradiation the blend ishomogenized to diffuse α-tocopherol from the α-tocopherol rich toα-tocopherol-poor regions and achieve oxidative stability throughout thepolymer.

The products and processes of this invention also apply to various typesof polymeric materials, for example, any polypropylene, any polyamide,any polyether ketone, or any polyolefin, includinghigh-density-polyethylene, low-density-polyethylene,linear-low-density-polyethylene, ultra-high molecular weightpolyethylene (UHMWPE), copolymers or mixtures thereof. The products andprocesses of this invention also apply to various types of hydrogels,for example, poly(vinyl alcohol), poly(ethylene glycol), poly(ethyleneoxide), poly(acrylic acid), poly(methacrylic acid), poly(acrylamide),copolymers or mixtures thereof, or copolymers or mixtures of these withany polyolefin. Polymeric materials, as used herein, also applies topolyethylene of various forms, for example, resin powder, flakes,particles, powder, or a mixture thereof, or a consolidated form derivedfrom any of the above. Polymeric materials, as used herein, also appliesto hydrogels of various forms, for example, film, extrudate, flakes,particles, powder, or a mixture thereof, or a consolidated form derivedfrom any of the above.

“Cross-linking Polymeric Materials” refers to polymeric materials, forexample, UHMWPE can be cross-linked by a variety of approaches,including those employing cross-linking chemicals (such as peroxidesand/or silane) and/or irradiation. Preferred approaches forcross-linking employ irradiation. Cross-linked UHMWPE also can beobtained through cold irradiation, warm irradiation, or melt irradiationaccording to the teachings of U.S. Pat. No. 5,879,400, U.S. Pat. No.6,641,617, and PCT/US97/02220.

“Consolidated polymeric material refers” to a solid, consolidated barstock, solid material machined from stock, or semi-solid form ofpolymeric material derived from any forms as described herein, forexample, resin powder, flakes, particles, or a mixture thereof, that canbe consolidated. The consolidated polymeric material also can be in theform of a slab, block, solid bar stock, machined component, film, tube,balloon, pre-form, implant, finished medical device or unfinisheddevice.

The term “non-permanent device” refers to what is known in the art as adevice that is intended for implantation in the body for a period oftime shorter than several months. Some non-permanent devices could be inthe body for a few seconds to several minutes, while other may beimplanted for days, weeks, or up to several months. Non-permanentdevices include catheters, tubing, intravenous tubing, and sutures, forexample.

“Pharmaceutical compound”, as described herein, refers to a drug in theform of a powder, suspension, emulsion, particle, film, cake, or moldedform. The drug can be free-standing or incorporated as a component of amedical device.

The term “pressure chamber” refers to a vessel or a chamber in which theinterior pressure can be raised to levels above atmospheric pressure.

The term “packaging” refers to the container or containers in which amedical device is packaged and/or shipped. Packaging can include severallevels of materials, including bags, blister packs, heat-shrinkpackaging, boxes, ampoules, bottles, tubes, trays, or the like or acombination thereof. A single component may be shipped in severalindividual types of package, for example, the component can be placed ina bag, which in turn is placed in a tray, which in turn is placed in abox. The whole assembly can be sterilized and shipped. The packagingmaterials include, but not limited to, vegetable parchments, multi-layerpolyethylene, Nylon 6, polyethylene terephthalate (PET), and polyvinylchloride-vinyl acetate copolymer films, polypropylene, polystyrene, andethylene-vinyl acetate (EVA) copolymers.

The term “sealing” refers to the process of isolating a chamber or apackage from the outside atmosphere by closing an opening in the chamberor the package. Sealing can be accomplished by a variety of means,including application of heat (for example, thermally-sealing), use ofadhesive, crimping, cold-molding, stapling, or application of pressure.

The term “blister packs” refers to a packaging comprised of a rigidplastic bowl with a lid or the like that is either peeled or puncturedto remove the packaged contents. The lid is often made of aluminum, or agas-permeable membrane such as a Tyvek. The blister packs are oftenblow-molded, a process where the plastic is heated above its deformationtemperature, at which point pressurized gas forces the plastic into therequired shape.

The term “heat-shrinkable packaging” refers to plastic films, bags, ortubes that have a high degree of orientation in them. Upon applicationof heat, the packaging shrinks down as the oriented chains retract,often wrapping tightly around the medical device.

The term “intervertebral disc system” refers to an artificial disc thatseparates the vertebrae in the spine. This system can either be composedof one type of material, or can be a composite structure, for example,cross-linked UHMWPE with metal edges.

The term “balloon catheters” refers to what is known in the art as adevice used to expand the space inside blood vessels or similar. Ballooncatheters are usually thin wall polymeric devices with an inflatabletip, and can expand blocked arteries, stents, or can be used to measureblood pressure. Commonly used polymeric balloons include, for example,polyether-block co-polyamide polymer (PeBAX®), Nylon, and polyethyleneterephthalate (PET) balloons. Commonly used polymeric material used inthe balloons and catheters include, for example, co-polymers ofpolyether and polyamide (for example, PeBAX®), Polyamides, Polyesters(for example, PET), and ethylene vinyl alcohol (EVA) used in catheterfabrication.

Medical device tubing: Materials used in medical device tubing,including an intravenous tubing include, polyvinyl chloride (PVC),polyurethane, polyolefins, and blends or alloys such as thermoplasticelastomers, polyamide/imide, polyester, polycarbonate, or various fluoropolymers.

The term “stent” refers to what is known in the art as a metallic orpolymeric cage-like device that is used to hold bodily vessels, such asblood vessels, open. Stents are usually introduced into the body in acollapsed state, and are inflated at the desired location in the bodywith a balloon catheter, where they remain.

“Melt transition temperature” refers to the lowest temperature at whichall the crystalline domains in a material disappear.

The term “interface” in this invention is defined as the niche inmedical devices formed when an implant is in a configuration where acomponent is in contact with another piece (such as a metallic or anon-metallic component), which forms an interface between the polymerand the metal or another polymeric material. For example, interfaces ofpolymer-polymer or polymer-metal are in medical prosthesis, such asorthopedic joints and bone replacement parts, for example, hip, knee,elbow or ankle replacements.

Medical implants containing factory-assembled pieces that are in closecontact with the polyethylene form interfaces. In most cases, theinterfaces are not readily accessible to ethylene oxide gas or the gasplasma during a gas sterilization process.

“Irradiation”, in one aspect of the invention, the type of radiation,preferably ionizing, is used. According to another aspect of theinvention, a dose of ionizing radiation ranging from about 25 kGy toabout 1000 kGy is used. The radiation dose can be about 25 kGy, about 50kGy, about 65 kGy, about 75 kGy, about 100 kGy, about 150, kGy, about200 kGy, about 300 kGy, about 400 kGy, about 500 kGy, about 600 kGy,about 700 kGy, about 800 kGy, about 900 kGy, or about 1000 kGy, or above1000 kGy, or any value thereabout or therebetween. Preferably, theradiation dose can be between about 25 kGy and about 150 kGy or betweenabout 50 kGy and about 100 kGy. These types of radiation, includinggamma and/or electron beam, kills or inactivates bacteria, viruses, orother microbial agents potentially contaminating medical implants,including the interfaces, thereby achieving product sterility. Theirradiation, which may be electron or gamma irradiation, in accordancewith the present invention can be carried out in air atmospherecontaining oxygen, wherein the oxygen concentration in the atmosphere isat least 1%, 2%, 4%, or up to about 22%, or any value thereabout ortherebetween. In another aspect, the irradiation can be carried out inan inert atmosphere, wherein the atmosphere contains gas selected fromthe group consisting of nitrogen, argon, helium, neon, or the like, or acombination thereof. The irradiation also can be carried out in avacuum. The irradiation also can be carried out at room temperature, orat between room temperature and the melting point of the polymericmaterial, or at above the melting point of the polymeric material.

In accordance with a preferred feature of this invention, theirradiation may be earned out in a sensitizing atmosphere. This maycomprise a gaseous substance which is of sufficiently small molecularsize to diffuse into the polymer and which, on irradiation, acts as apolyfunctional grafting moiety. Examples include substituted orunsubstituted polyunsaturated hydrocarbons; for example, acetylenichydrocarbons such as acetylene; conjugated or unconjugated olefinichydrocarbons such as butadiene and (meth)acrylate monomers; sulphurmonochloride, with chloro-tri-fluoroethylene (CTFE) or acetylene beingparticularly preferred. By “gaseous” is meant herein that thesensitizing atmosphere is in the gas phase, either above or below itscritical temperature, at the irradiation temperature.

“Metal Piece”, in accordance with the invention, the piece forming aninterface with polymeric material is, for example, a metal. The metalpiece in functional relation with polyethylene, according to the presentinvention, can be made of a cobalt chrome alloy, stainless steel,titanium, titanium alloy or nickel cobalt alloy, for example.

“Non-metallic Piece”, in accordance with the invention, the pieceforming an interface with polymeric material is, for example, anon-metal. The non-metal piece in functional relation with polyethylene,according to the present invention, can be made of ceramic material, forexample.

The term “inert atmosphere” refers to an environment having no more than1% oxygen and more preferably, an oxidant-free condition that allowsfree radicals in polymeric materials to form cross links withoutoxidation during a process of sterilization. An inert atmosphere is usedto avoid O₂, which would otherwise oxidize the medical device comprisinga polymeric material, such as UHMWPE. Inert atmospheric conditions suchas nitrogen, argon, helium, or neon are used for sterilizing polymericmedical implants by ionizing radiation.

Inert atmospheric conditions such as nitrogen, argon, helium, neon, orvacuum are also used for sterilizing interfaces of polymeric-metallicand/or polymeric-polymeric in medical implants by ionizing radiation.

Inert atmospheric conditions also refer to an inert gas, inert fluid, orinert liquid medium, such as nitrogen gas or silicon oil.

“Anoxic environment” refers to an environment containing gas, such asnitrogen, with less than 21%-22% oxygen, preferably with less than 2%oxygen. The oxygen concentration in an anoxic environment also can be atleast about 1%, 2%, 4%, 6%, 8%, 10%, 12% 14%, 16%, 18%, 20%, or up toabout 22%, or any value thereabout or therebetween.

The term “vacuum” refers to an environment having no appreciable amountof gas, which otherwise would allow free radicals in polymeric materialsto form cross links without oxidation during a process of sterilization.A vacuum is used to avoid O₂, which would otherwise oxidize the medicaldevice comprising a polymeric material, such as UHMWPE. A vacuumcondition can be used for sterilizing polymeric medical implants byionizing radiation.

A vacuum condition can be created using a commercially available vacuumpump. A vacuum condition also can be used when sterilizing interfaces ofpolymeric-metallic and/or polymeric-polymeric in medical implants byionizing radiation.

“Residual free radicals” refers to free radicals that are generated whena polymer is exposed to ionizing radiation such as gamma or e-beamirradiation. While some of the free radicals recombine with each otherto from cross-links, some become trapped in crystalline domains. Thetrapped free radicals are also known as residual free radicals.

According to one aspect of the invention, the levels of residual freeradicals in the polymer generated during an ionizing radiation (such asgamma or electron beam) is preferably determined using electron spinresonance and treated appropriately to reduce the free radicals.

“Sterilization”, one aspect of the present invention discloses a processof sterilization of medical implants containing polymeric material, suchas cross-linked UHMWPE. The process comprises sterilizing the medicalimplants by ionizing sterilization with gamma or electron beamradiation, for example, at a dose level ranging from about 25-70 kGy, orby gas sterilization with ethylene oxide or gas plasma.

Another aspect of the present invention discloses a process ofsterilization of medical implants containing polymeric material, such ascross-linked UHMWPE. The process comprises sterilizing the medicalimplants by ionizing sterilization with gamma or electron beamradiation, for example, at a dose level ranging from 25-200 kGy. Thedose level of sterilization is higher than standard levels used inirradiation. This is to allow cross-linking or further cross-linking ofthe medical implants during sterilization.

In another aspect, the invention discloses a process of sterilizingmedical implants containing polymeric material, such as cross-linkedUHMWPE, that is in contact with another piece, including polymericmaterial consolidated by compression molding to another piece, therebyforming an interface and an interlocked hybrid material, comprisingsterilizing an interface by ionizing radiation; heating the medium toabove the melting point of the irradiated UHMWPE (above about 137° C.)to eliminate the crystalline matter and allow for therecombination/elimination of the residual free radicals; and sterilizingthe medical implant with a gas, for example, ethylene oxide or gasplasma.

One aspect of the present invention discloses a process of increasingthe uniformity of the antioxidant following doping in polymericcomponent of a medical implant during the manufacturing process byheating for a time period depending on the melting temperature of thepolymeric material. For example, the preferred temperature is about 137°C. or less. Another aspect of the invention discloses a heating stepthat can be carried in the air, in an atmosphere, containing oxygen,wherein the oxygen concentration is at least about 1%, 2%, 4%, or up toabout 22%, or any value thereabout or therebetween. In another aspect,the invention discloses a heating step that can be carried while theimplant is in contact with an inert atmosphere, wherein the inertatmosphere contains gas selected from the group consisting of nitrogen,argon, helium, neon, or the like, or a combination thereof. In anotheraspect, the invention discloses a heating step that can be carried whilethe implant is in contact with a non-oxidizing medium, such as an inertfluid medium, wherein the medium contains no more than about 1% oxygen.In another aspect, the invention discloses a heating step that can becarried while the implant is in a vacuum.

In theoretical thermodynamics, “adiabatic heating” refers to an absenceof heat transfer to the surroundings. In the practice, such as in thecreation of new polymeric materials, adiabatic heating refers tosituations where the vast majority of thermal energy is imparted on thestarting material and is not transferred to the surroundings. Such canbe achieved by the combination of insulation, irradiation dose rates andirradiation time periods, as disclosed herein and in the documents citedherein. Thus, what may approach adiabatic heating in the theoreticalsense achieves it in the practical sense. However, not all warmirradiation refers to an adiabatic heating. Warm irradiation also canhave non-adiabatic or partially (such as 10-75% of the heat generatedare lost to the surroundings) adiabatic heating.

In another aspect of this invention, there is described the heatingmethod of implants to increase the uniformity of the antioxidant. Themedical device comprising a polymeric raw material, such as UHMWPE, isgenerally heated to a temperature of about 137° C. or less following thestep of doping with the antioxidant. The medical device is kept heatedin the inert medium until the desired uniformity of the antioxidant isreached.

The term “below melting point” or “below the melt” refers to atemperature below the melting point of a polymeric material, forexample, polyethylene such as UHMWPE. The term “below melting point” or“below the melt” refers to a temperature less than about 145° C., whichmay vary depending on the melting temperature of the polyethylene, forexample, about 145° C., 140° C. or 135° C., which again depends on theproperties of the polyethylene being treated, for example, molecularweight averages and ranges, batch variations, etc. The meltingtemperature is typically measured using a differential scanningcalorimeter (DSC) at a heating rate of 10° C. per minute. The peakmelting temperature thus measured is referred to as melting point, alsoreferred as transition range in temperature from crystalline toamorphous phase, and occurs, for example, at approximately 137° C. forsome grades of UHMWPE. It may be desirable to conduct a melting study onthe starting polyethylene material in order to determine the meltingtemperature and to decide upon an irradiation and annealing temperature.Generally, the melting temperature of polymeric material is increasedwhen the polymeric material is under pressure.

The term “annealing” refers to a thermal treatment condition inaccordance with the invention. Annealing generally refers to heating thepolymeric material at a temperature below or above its peak meltingpoint. Annealing time can be at least 1 minute to several weeks long. Inone aspect the annealing time is about 4 hours to about 48 hours,preferably 24 to 48 hours and more preferably about 24 hours. “Annealingtemperature” refers to the thermal condition for annealing in accordancewith the invention.

The term “contacted” includes physical proximity with or touching suchthat the sensitizing agent can perform its intended function.Preferably, a polyethylene composition or pre-form is sufficientlycontacted such that it is soaked in the sensitizing agent, which ensuresthat the contact is sufficient. Soaking is defined as placing the samplein a specific environment for a sufficient period of time at anappropriate temperature, for example, soaking the sample in a solutionof an antioxidant. The environment is heated to a temperature rangingfrom room temperature to a temperature below the melting point of thematerial. The contact period ranges from at least about 1 minute toseveral weeks and the duration depending on the temperature of theenvironment.

The term “non-oxidizing” refers to a state of polymeric material havingan oxidation index (A. U.) of less than about 0.5 following agingpolymeric materials for 5 weeks in air at 80° C. oven. Thus, anon-oxidizing cross-linked polymeric material generally shows anoxidation index (A. U.) of less than about 0.5 after the aging period.

The term “surface” of a polymeric material refers generally to theexterior region of the material having a thickness of about 1.0 μm toabout 2 cm, preferably about 1.0 mm to about 5 mm, more preferably about2 mm of a polymeric material or a polymeric sample or a medical devicecomprising polymeric material.

The term “bulk” of a polymeric material refers generally to an interiorregion of the material having a thickness of about 1.0 μm to about 2 cm,preferably about 1.0 mm to about 5 mm, more preferably about 2 mm, fromthe surface of the polymeric material to the center of the polymericmaterial. However, the bulk may include selected sides or faces of thepolymeric material including any selected surface, which may becontacted with a higher concentration of antioxidant.

Although the terms “surface” and “bulk” of a polymeric materialgenerally refer to exterior regions and the interior regions,respectively, there generally is no discrete boundary between the tworegions. But, rather the regions are more of a gradient-like transition.These can differ based upon the size and shape of the object and theresin used.

The term “doping” refers to a general process well known in the art(see, for example, U.S. Pat. Nos. 6,448,315 and 5,827,904). In general,it refers to incorporating an additive ‘dopant’ into the polymericmaterial in quantities less than 50%. In this connection, dopinggenerally refers to contacting a polymeric material with an antioxidantunder certain conditions, as set forth herein, for example, dopingUHMWPE with an antioxidant under supercritical conditions.

In certain embodiments of the present invention in which doping ofantioxidant is carried out at a temperature above the melting point ofthe polymeric material, the antioxidant-doped polymeric material can befurther heated above the melt or annealed to eliminate residual freeradicals after irradiation. Melt-irradiation of polymeric material inpresence of an antioxidant, such as vitamin E, can change thedistribution of the vitamin E concentration and also can change themechanical properties of the polymeric material. These changes can beinduced by changes in crystallinity and/or by the plasticization effectof vitamin E at certain concentrations.

According to one embodiment, the surface of the polymeric material iscontacted with little or no antioxidant and bulk of the polymericmaterial is contacted with a higher concentration of antioxidant.

According to another embodiment, the surface of the polymeric materialis contacted with no antioxidant and bulk of the polymeric material iscontacted with a higher concentration of antioxidant.

According to one embodiment, the bulk of the polymeric material iscontacted with little or no antioxidant and surface of the polymericmaterial is contacted with a higher concentration of antioxidant.

According to another embodiment, the bulk of the polymeric material iscontacted with no antioxidant and surface of the polymeric material iscontacted with a higher concentration of antioxidant.

According to another embodiment, the surface of the polymeric materialand the bulk of the polymeric material are contacted with the sameconcentration of antioxidant.

According to one embodiment, the surface of the polymeric material maycontain from about 0 wt % to about 50 wt % antioxidant, preferably about0.001 wt % to about 10 wt %, preferably between about 0.01 wt % to about0.5 wt %, more preferably about 0.2 wt %. According to anotherembodiment, the bulk of the polymeric material may contain from about 0wt % to about 50 wt %, preferably about 0.001 wt % to about 10 wt %,preferably between about 0.01 wt % to about 0.5 wt %, more preferablyabout 0.2 wt %, preferably between about 0.2 wt % and about 1% wt %,preferably about 0.5 wt %.

According to another embodiment, the surface of the polymeric materialand the bulk of the polymeric material contain the same concentration ofantioxidant.

More specifically, consolidated polymeric material can be doped with anantioxidant by soaking the material in a solution of the antioxidant.This allows the antioxidant to diffuse into the polymer. For instance,the material can be soaked in 100% antioxidant. The material also can besoaked in an antioxidant solution where a carrier solvent can be used todilute the antioxidant concentration. To increase the depth of diffusionof the antioxidant, the material can be doped for longer durations, athigher temperatures, at higher pressures, and/or in presence of asupercritical fluid.

The antioxidant can be diffused to a depth of about 5 mm or more fromthe surface, for example, to a depth of about 3-5 mm, about 1-3 mm, orto any depth thereabout or therebetween.

The doping process can involve soaking of a polymeric material, medicalimplant or device with an antioxidant, such as vitamin E, for about halfan hour up to several days, preferably for about one hour to 24 hours,more preferably for one hour to 16 hours. The antioxidant can be at roomtemperature or heated up to about 137° C. and the doping can be carriedout at room temperature or at a temperature up to about 137° C.Preferably the antioxidant solution is heated to a temperature betweenabout 100° C. and 135° C. or between about 110° C. and 130° C., and thedoping is carried out at a temperature between about 100° C. and 135° C.or between about 110° C. and 130° C. More preferably, the antioxidantsolution is heated to about 120° C. and the doping is carried out atabout 120° C.

Doping with α-tocopherol through diffusion at a temperature above themelting point of the irradiated polyethylene (for example, at atemperature above 137° C.) can be carried out under reduced pressure,ambient pressure, elevated pressure, and/or in a sealed chamber, forabout 0.1 hours up to several days, preferably for about 0.5 hours to 6hours or more, more preferably for about 1 hour to 5 hours. Theantioxidant can be at a temperature of about 137° C. to about 400° C.,more preferably about 137° C. to about 200° C., more preferably about137° C. to about 160° C.

The doping and/or the irradiation steps can be followed by an additionalstep of “homogenization”, which refers to a heating step in air or inanoxic environment to improve the spatial uniformity of the antioxidantconcentration within the polymeric material, medical implant or device.Homogenization also can be carried out before and/or after theirradiation step. The heating may be carried out above or below or atthe peak melting point. Antioxidant-doped or -blended polymeric materialcan be homogenized at a temperature below or above or at the peakmelting point of the polymeric material for a desired period of time,for example, the antioxidant-doped or -blended polymeric material can behomogenized for about an hour to several days at room temperature toabout 400° C. Preferably, the homogenization is carried out at 90° C. to180° C., more preferably 100° C. to 137° C., more preferably 120° C. to135° C., most preferably 130° C. Homogenization is preferably carriedout for about one hour to several days to two weeks or more, morepreferably about 12 hours to 300 hours or more, more preferably about280 hours, or more preferably about 200 hours. More preferably, thehomogenization is carried out at about 130° C. for about 36 hours or atabout 120° C. for about 24 hours. The polymeric material, medicalimplant or device is kept in an inert atmosphere (nitrogen, argon,and/or the like), under vacuum, or in air during the homogenizationprocess. The homogenization also can be performed in a chamber withsupercritical fluids such as carbon dioxide or the like. The pressure ofthe supercritical fluid can be about 1000 to about 3000 psi or more,more preferably about 1500 psi. It is also known that pressurizationincreases the melting point of UHMWPE. A higher temperature than 137° C.can be used for homogenization below the melting point if appliedpressure has increased the melting point of UHMWPE.

The polymeric material, medical implant or device is kept in an inertatmosphere (nitrogen, argon, and/or the like), under vacuum, or in airduring the homogenization process. The homogenization also can beperformed in a chamber with supercritical fluids such as carbon dioxideor the like. The pressure of the supercritical fluid can be 1000 to 3000psi or more, more preferably about 1500 psi. The homogenization can beperformed before and/or after and/or during the diffusion of theantioxidant.

The terms “extraction” or “elution” of antioxidant from antioxidantcontaining consolidated polymeric material refers to partial or completeremoval of the antioxidant, for example, vitamin E, from theconsolidated polymeric material by various processes disclosed herein.For example, the extraction or elution of antioxidant can be done with acompatible solvent that dissolves the antioxidant contained in theconsolidated polymeric material. Such solvents include, but not limitedto, a hydrophobic solvent, such as hexane, heptane, or a longer chainalkane; an alcohol such as ethanol, any member of the propanol orbutanol family or a longer chain alcohol; or an aqueous solution inwhich an antioxidant, such as vitamin E is soluble. Such a solvent alsocan be made by using an emulsifying agent such as Tween 80 or ethanol.The extraction or elution of antioxidant from antioxidant containingconsolidated polymeric material is generally done prior to placementand/or implantation of the polymeric material, or a medical implantcomprising the antioxidant containing consolidated polymeric material,into the body.

Extraction of α-tocopherol from a polyethylene at a temperature belowthe melting temperature of the polyethylene can be achieved by placingthe polyethylene in an open or in a sealed chamber. A solvent or anaqueous solution also can be added in order to extract the α-tocopherolfrom polyethylene. The chamber is then heated below the melting point ofthe polyethylene, preferably between about room temperature to near themelting point, more preferably about 100° C. to about 137° C., morepreferably about 120° C., or more preferably about 130° C. If a sealedchamber is used, there will be an increase in pressure during heating.Because the polyethylene is cross-linked, only the crystalline regionsmelt. The chemical cross-links between chains remain intact and allowthe polyethylene to maintain its shape throughout the process despitesurpassing its melting temperature. Increasing pressure increases themelting temperature of the polymeric material. In this case,homogenization below the melt is performed under pressure above 137° C.,for example at about 145° C.

Extraction of α-tocopherol from a polyethylene at a temperature abovethe melting temperature of the polyethylene can be achieved by placingthe polyethylene in an open or in a sealed chamber. A solvent or anaqueous solution also can be added in order to extract the α-tocopherolfrom polyethylene. The chamber is then heated above the melting point ofthe polyethylene, preferably between about 137° C. to about 400° C.,more preferably about 137° C. to about 200° C., more preferably about137° C., or more preferably about 160° C. If a sealed chamber is used,there will be an increase in pressure during heating. Because thepolyethylene is cross-linked, only the crystalline regions melt. Thechemical cross-links between chains remain intact and allow thepolyethylene to maintain its shape throughout the process despitesurpassing its melting temperature. Since crystallites pose a hindranceto diffusion of α-tocopherol in polyethylene, increasing the temperatureabove the melting point should increase the rate of extraction ofα-tocopherol. Increasing pressure increases the melting temperature ofthe polymeric material.

The term “plasticizing agent” refers to what is known in the art, amaterial with a molecular weight less than that of the base polymer, forexample vitamin E (α-tocopherol) in unirradiated or cross-linkedultrahigh molecular weight polyethylene or low molecular weightpolyethylene in high molecular weight polyethylene, in both casesultrahigh molecular weight polyethylene being the base polymer. Theplasticizing agent is typically added to the base polymer in less thanabout 20 weight percent. The plasticizing agent generally increasesflexibility and softens the polymeric material.

The term “plasticization” or “plasticizing” refers to the propertiesthat a plasticizing agent imparts on the polymeric material to which ithas been contacted with. These properties may include but are notlimited to increased elongation at break, reduced stiffness andincreased ductility.

The invention is further described by the following examples, which donot limit the invention in any manner.

EXAMPLES

Vitamin E: Vitamin E (Acros™ 99% D-α-Tocopherol, Fisher Brand), was usedin the experiments described herein, unless otherwise specified. Thevitamin E used is very light yellow in color and is a viscous fluid atroom temperature. Its melting point is 2-3° C.

Example 1 DCM of UHMWPE Pucks Containing α-Tocopherol-Rich Regions andα-Tocopherol-Poor Regions

Two puck-shaped pieces of UHMWPE, both 2.5″ in diameter, were directcompression molded (DCM). One puck was 1″ thick, the other one was 1.5″thick. The 1″ thick puck was produced using a standard molding cycle inwhich the bottom half of the mold was filled with GUR 1050 powdercontaining 0.5 wt % α-tocopherol and the top half with virgin GUR 1050powder. The 1.5″ thick puck was produced using a modified molding cycle,in which the bottom half of the mold was filled with GUR 1050 powdercontaining 0.5 wt % α-tocopherol and compressed at room temperatureunder a pressure of 1220 psi. Following release of the pressure, the tophalf of the mold was filled with virgin GUR 1050 powder followed by astandard DCM cycle. A picture of the 1.5″ thick puck is shown in FIG.3A.

A thin film was microtomed across the sample from both of the pucks forFTIR analysis of the Vitamin E Index (VEI) as a function of depth withinthe sample. The thin cross-section was then analyzed using an infraredmicroscope. Infrared spectra were collected as a function of depth awayfrom one of the edges that coincided with the free surface of thesample. The absorbance between 1226 and 1295 cm⁻¹ is characteristic ofα-tocopherol (vitamin E) and polyethylene does not absorb near thesefrequencies. For polyethylene, the 1895 cm⁻¹ wave number for the CH₂rocking mode is a typical choice as an internal reference. Thenormalized value, which is the ratio of the integrated absorbances of1260 cm⁻¹ and 1895 cm⁻¹, is an index that provides a relative metric ofα-tocopherol composition in polyethylene and is termed the vitamin Eindex.

A plot of VEI as a function of depth (measured through the thickness ofthe puck) is shown in FIG. 3B. For both samples, the data show a smooth,linear transition from a constant VEI (˜0.12) at the left of the plot toa VEI value of zero at the right of the plot. The distance over whichthe VEI transitions to zero is approximately 3 mm, which is relativelysmall and indicates that parts with α-tocopherol-rich andα-tocopherol-poor regions can be molded using a standard DCM cyclewithout excessive bleeding of the α-tocopherol from the blended to thevirgin regions.

The pucks were subjected to a series of processing steps, whichincluded:

1. Irradiation via electron beam to a dose of 100 kGy;

2. Annealing (1.5″ puck) or doping/homogenization (1″ puck) to infusevirgin polyethylene regions with α-tocopherol; and

3. Accelerated aging for 2 weeks in oxygen at a pressure of 5 atm (ASTMF2003-02).

Following aging, the samples were subjected to pin-on-disk wear testing,with the articulating surface of the pin corresponding to the initiallyvirgin polyethylene side of the puck.

In FIG. 4A, the Vitamin E Index (VEI) for the 1.5″ thick puck at variousstages of processing is shown. The effect of irradiation to 100 kGy isto reduce significantly the measured Vitamin E Index in the region withα-tocopherol, from a value of 0.11-0.12 before irradiation to a value ofapproximately 0.04 after irradiation. Subjecting the sample to anannealing step, whereby the sample was heated to 130° C. under Argon andheld for 62 hours, did not lead to significant penetration ofα-tocopherol into the virgin polyethylene region. This indicates thatirradiation may facilitate attachment of the α-tocopherol to the UHMWPEchains, thereby stopping diffusion of α-tocopherol in this sample. InFIG. 49, VEI data are plotted for the 1″ thick puck, which was subjectedto irradiation, followed by doping in α-tocopherol at 120° C. for 3hours and homogenization at 130° C. for 36 hours. The VEI data show thatα-tocopherol diffused into the sample from both sides, and the side thatalready contained α-tocopherol has higher VEI values after doping. Thereis complete penetration of the part by α-tocopherol after thisrelatively short doping and homogenization cycle. (For comparison,complete penetration of an initially virgin puck of UHMWPE would requireapproximately 200 hours of homogenization). The effect of aging, in thiscase, is to reduce significantly the values of the Vitamin E indexthroughout the entire sample.

In order to determine the extent of oxidation in the samples, a modifiedcalculation protocol was utilized, which is illustrated in FIG. 5. Thereare three FTIR spectra plotted in FIG. 5: one shows a typical spectrumfor an unaged UHMWPE sample, one shows for an aged UHMWPE samplecontaining no α-tocopherol, and finally one shows for an aged samplecontaining a significant amount of α-tocopherol. The effect of oxidationon the FTIR spectrum of UHMWPE in the absence of α-tocopherol ismanifested as a broad peak in the wavenumber range of 1680 cm⁻¹-1780cm⁻¹ (due to the formation of carbonyl groups on the UHMWPE chains). Inthe unaged sample, no peaks are observed within this wavenumber range,indicating no measureable oxidation. In the aged sample containing noα-tocopherol, a broad peak is observed within the range 1680 cm⁻¹-1780cm⁻¹. The spectrum for the UHMWPE sample containing α-tocopherol has anadditional peak at 1680 cm⁻¹, which is due to the formation of thequinone version of α-tocopherol (as shown in FIG. 5). The lowerwavenumber associated with the quinone is due to the conjugated natureof its carbonyl groups. The value of the oxidation index of UHMWPE wasdetermined to be the integrated region between 1705 cm⁻¹-1780 cm⁻¹,thereby avoiding the quinone peak. An additional parameter wascalculated, here referred to as the Vitamin E Quinone Index (VEQI),which was the integrated region between 1660 cm⁻¹-1700 cm⁻¹.

In FIG. 6, the values of the oxidation index (OI) of UHMWPE, the VitaminE index (VEI), and the Vitamin E Quinone Index (VEQI) are plotted forboth the 1.5″ annealed sample after aging (see FIG. 6A) and for the 1″doped sample after aging (see FIG. 6B). In FIG. 6A, the VEI values, asshown earlier, are relatively constant for the first 15 mm, followed bya gradual drop to zero and a subsequent region of virgin UHMWPE. Theeffect of accelerated aging on the OI appears to be insignificant. Inthe α-tocopherol-containing region of the sample, the OI values arerelatively constant, centered around a value of ˜0.03. Only at the edgeof the sample containing no α-tocopherol (19-22 mm) is there a trend inOI. This is the portion of the sample containing no α-tocopherol, thusan increase in OI is not surprising, however it is not large. Regardingthe VEQI, all values are very small (≦0.01), however there is a trendfrom a higher, slightly positive value in the region containingα-tocopherol, to a slightly negative value in the region withoutα-tocopherol. Thus it appears that there is conversion of theα-tocopherol to its quinone form at a relatively small rate during theaging process.

In FIG. 6B, the VEQI values show a more significant correlation with theVEI values. In particular, in the region where the VEI values arehighest, near the surfaces, the VEQI values are also highest, indicatinggreater conversion to the quinone form of α-tocopherol with greaterconcentrations of α-tocopherol. The 01 values do not show a significanttrend; they are slightly higher toward the right-hand side of the plot,where the virgin UHMWPE region was initially, but overall they aresmall, much like the value in FIG. 6A for the annealed sample. Perhapsthe most significant result is that oxidation of the UHMWPE does notoccur in the regions containing α-tocopherol, even after acceleratedaging.

In FIG. 7, FTIR spectra for the 1.5″ annealed sample after aging areplotted to show the size of the quinone peak as a function of depth. Onecan see a monotonic trend in the size of the peak, as distance into thesample is increased. It is also apparent that the typical oxidation peakfor UHMWPE (1730 cm⁻¹) is not significant, definitively showing theefficacy of α-tocopherol stabilization of UHMWPE.

Pin-on-disk wear test data for aged pins after 0.5 million cycles areshown in Table 1. Data for the sample annealed at 130° C. and the samplethat was doped and homogenized are shown. An additional sample, whichwas annealed at 145° C., followed by aging, is also shown. Overall, thewear rates are relatively similar, with the values close to a weightloss of 2 mg/MC. These values are comparable to what is observed inhighly cross-linked UHMWPE without α-tocopherol (S. M. Kurtz; O. K.Muratoglu; M. Evans; A. A. Eddin, “Advances in the processing,sterilization, and cross-linking of ultra-high molecular weightpolyethylene for total joint arthroplasty”, Biomaterials, 20 (1999)1659-1688).

TABLE 1 Pin-on-disk wear data for aged pins after 0.5 million cyclesProcessing steps Weight Loss Projected Wear Rate Annealed at 130° C.−0.80 mg −1.60 mg/MC Doped and homogenized −0.90 mg −1.80 mg/MCMelt-annealed at 145° C. −1.03 mg −2.06 mg/MC

Example 2 DCM of Acetabular Component with Wear-Resistant BearingSurface and Tough Interior

An acetabular shell of a porous metal such as tantalum, titanium, orother, or a non-porous metal, is used. GUR 1050 UHMWPE powder blendedwith α-tocopherol is fully consolidated or partially consolidated intothe metal shell. UHMWPE diffusion into the metal is self-limiting. OtherUHMWPE resins such as GUR 1020 are also used. The concentration ofα-tocopherol in the powder blend is between about 0.005 and about 20 wt%, preferably between 0.05 and 5.0 wt %, preferably about 0.3 wt %,preferably about 0.5 wt %, or preferably about 1 wt %. The plunger usedto pack the blended powder into the metal component is large enough toallow additional powder to be added in a second consolidation process,during which virgin GUR 1050 powder or GUR1050 with low amount ofvitamin E is added over the blended GUR 1050 layer already in the shell.The second consolidation process is then performed using a plunger thatis smaller than the final cup size of the component. The time ofconsolidation and the thickness of the virgin UHMWPE layer arecontrolled so that the thickness of the virgin layer is between about0.1 mm and 10 mm, preferably 1 mm, preferably 2 mm, preferably 3 mm, orpreferably 5 mm, or preferably more than 10 mm.

The fully consolidated component is irradiated using ionizing radiationsuch as gamma, electron-beam, or x-ray to a dose level between about 1and about 10,000 kGy, preferably 25 to 200 kGy, preferably 50 to 150kGy, preferably 65 kGy, preferably 85 kGy, or preferably 100 kGy. Theirradiated acetabular component is then doped with α-tocopherol byplacing the component in an α-tocopherol bath at room temperature or atan elevated temperature for a given amount of time, followed by ahomogenization step under inert gas at room temperature or at anelevated temperature for a given amount of time. Table 2 is a list ofpreferred doping and homogenization times for select virgin UHMWPE layerthicknesses doped and homogenized at T=120° C. At higher temperaturesthe doping times are shorter and the homogenization times are shorter aswell. Doping and homogenization times are longer if more α-tocopherol isdesirable to have in the polyethylene.

After doping/homogenization, the UHMWPE is machined to its final shape.The machining is done in such a way that the thickness of thewear-resistant cross-linked UHMWPE layer at the acetabular cup surfaceis at least 0.1 mm, at least 0.2 mm, at least 1 mm, at least 2 mm, or atleast 5 mm. The thickness of the uncross-linked, tough bulk layer is atleast 0.5 mm, at least 1 mm, at least 2 mm, at least 5 mm, at least 10mm, or at least 15 mm.

The finished component is then packaged under inert gas or under vacuumand subjected to sterilization. Sterilization is performed usingionizing radiation such as gamma, electron-beam, or x-ray to a doselevel between 1 and 1000 kGy, preferably 10 to 200 kGy, preferably 25kGy, preferably 40 kGy, or preferably 50 kGy. Alternatively the implantis packaged with gas permeable packaging and sterilized using a gas suchas ethylene oxide or gas plasma.

TABLE 2 Doping and homogenization times for different virgin UHMWPElayer thickness. (For doping and homogenization performed at 120° C.)Homogenization Thickness of virgin layer (mm) Doping time (hr) time (hr)1 0.17 4 3 0.33 9 6 2.5 40 9 3 45

Example 3 DCM of Tibial Component with Wear-Resistant Bearing Surfaceand Tough Interior

A tibial base plate made from a porous metal such as tantalum, titanium,or other, or a non-porous metal, is used. GUR 1050 UHMWPE powder blendedwith α-tocopherol is fully consolidated or partially consolidated ontothe base plate. UHMWPE diffusion into the porous metal is self-limiting.Other UHMWPE resins such as GUR 1020 are also used. The concentration ofα-tocopherol in the powder blend is between about 0.005 and about 20 wt%, preferably between 0.05 and 5.0 wt %, preferably about 0.3 wt %,preferably about 0.5 wt %, or preferably about 1 wt %. Virgin GUR 1050powder or GUR1050 powder blended with low amount of vitamin E is thenadded over the blended GUR1050 layer already present. A secondconsolidation process is then performed using to produce a total UHMWPElayer that is larger the final UHMWPE thickness in the finishedcomponent. The time of consolidation and the thickness of the virginUHMWPE layer is controlled so that the thickness of the virgin layer isbetween about 0.1 mm and 10 mm, preferably 1 mm, preferably 2 mm,preferably 3 mm, or preferably 5 mm, or preferably more than 10 mm.

The fully consolidated component is irradiated using ionizing radiationsuch as gamma, electron-beam, or x-ray to a dose level between 1 and10,000 kGy, preferably 25 to 200 kGy, preferably 50 to 150 kGy,preferably 65 kGy, preferably 85 kGy, or preferably 100 kGy. Theirradiated tibial component is then doped with α-tocopherol by placingthe component in an α-tocopherol bath at room temperature or at anelevated temperature for a given amount of time, followed by ahomogenization step under inert gas at room temperature or at anelevated temperature for a given amount of time. Table 1 is a list ofpreferred doping and homogenization times for select virgin UHMWPE layerthicknesses doped and homogenized at T=120° C. At higher temperaturesthe doping times are shorter and the homogenization times are shorter aswell. Doping and homogenization times are longer if more α-tocopherol isdesirable to have in the polyethylene.

After doping/homogenization, the UHMWPE is machined to its final shape.The machining is done in such a way that the thickness of thewear-resistant cross-linked UHMWPE layer at the articular surface of thetibial component is at least 0.1 mm, at least 0.2 mm, at least 1 mm, atleast 2 mm, or at least 5 mm. The thickness of the uncross-linked, toughbulk layer is at least 0.5 mm, at least 1 mm, at least 2 mm, at least 5mm, at least 10 mm, at least 15 mm, or at least 25 mm.

The finished component is then packaged under inert gas or under vacuumand subjected to sterilization. Sterilization is performed usingionizing radiation such as gamma, electron-beam, or x-ray to a doselevel between 1 and 1000 kGy, preferably 10 to 200 kGy, preferably 25kGy, preferably 40 kGy, or preferably 50 kGy. Alternatively the implantis packaged with gas permeable packaging and sterilized using a gas suchas ethylene oxide or gas plasma.

Example 4 Consolidation of UHMWPE/Vitamin E in Anoxic Environment

α-tocopherol is dissolved in ethanol to create a solution. GUR1050polyethylene resin is degassed either in vacuum or is kept in an anoxicenvironment to substantially remove the dissolved oxygen. Theα-tocopherol-ethanol solution is then dry-blended with GUR1050polyethylene resin. Two batches are prepared, one with degassed GUR1050and the other with the as-received GUR1050 polyethylene resin. Thedry-blended mixtures are then separately consolidated on a Carverlaboratory bench press. Consolidation can be carried out in an anoxicenvironment to minimize the discoloration of the consolidated stock.

Example 5 Cross-Link Density of Blended and Irradiated UHMWPE (2003)

GUR 1050 powder was blended with α-tocopherol and consolidated.Consolidated GUR 1050 UHMWPE powder (consolidated without α-tocopherol)was used as virgin (control) material. The concentrations at whichα-tocopherol was incorporated in the UHMWPE were 0.02, 0.05, 0.1, 0.3and 1.0 wt/wt %. The blends were first prepared in 5 wt % forconsistency, after which they were diluted down to their respectiveconcentrations by adding UHMWPE powder. The molded blocks containing0.1, 0.3 and 1.0 wt % were packaged under vacuum and γ-irradiated to 25,65, 100, 150 and 200 kGy and the molded blocks containing 0.02 and 0.05wt % were packaged and γ-irradiated to 150 and 200 kGy.

Cross-link density measurements were performed with a thermal mechanicalanalyzer (TMA) (DMA 7e, Perkin Elmer, Wellesley, Mass.). Thin sectionswere machined out of virgin, and α-tocopherol-blended and irradiatedUHMWPE (thickness 3.2 mm). These thin sections were melted at 170° C.under flowing nitrogen to remove residual stresses from theconsolidation process that might result in additional swelling. Smallsections were cut out by razor blade from these thin sections to beanalyzed (approximately 3 mm by 3 mm) These small pieces were placedunder the quartz probe of the TMA and the initial height of the samplewas recorded. Then, the probe was immersed in xylene, which wassubsequently heated to 130° C. and held for at least 100 minutes. TheUHMWPE samples swelled in hot xylene until equilibrium was reached. Thefinal height was recorded. The cross-link density of the blends wascalculated as described previously (see Muratoglu et al., Unified WearModel for Highly Crosslinked Ultra-high Molecular Weight Polyethylenes(UHMWPE). Biomaterials, 1999. 20(16): p. 1463-1470) and are reported asmol/m³.

The cross-link density of these virgin and blended and subsequentlyirradiated UHMWPE are shown in FIG. 8. These results show clearly thatincreasing vitamin E concentration decreases cross-linking in UHMWPEwhen present during irradiation. It also showed that at 0.05 wt %, thepresence of vitamin E did not significantly affect cross-linking at 150and 200 kGy compared to virgin UHMWPE (p=0.6 and 0.3, respectively).Since wear rate is dependent on cross-link density, the wear rate ofthis UHMWPE would be expected to be similar to virgin, irradiatedUHMWPE.

Example 6 Wear Rate of Blended and Irradiated UHMWPE

GUR 1050 powder was blended with α-tocopherol and consolidated.Consolidated GUR 1050 UHMWPE powder (consolidated without α-tocopherol)was used as virgin (control) material. The concentrations at whichα-tocopherol was incorporated in the UHMWPE were 0.1, and 0.3 wt/wt %.The blends were first prepared in 5 wt % for consistency, after whichthey were diluted down to their respective concentrations by addingUHMWPE powder. These molded blocks were packaged and γ-irradiated to 100kGy.

Three cylindrical samples (9 mm in diameter and 13 mm in length) out ofeach of the three irradiated blocks (virgin, 0.1%, and 0.3 wt %) wereused for POD wear testing. These pins were accelerated aged at 80° C. inair for 5 weeks and tested on a bi-directional POD tester at a frequencyof 2 Hz for 2 million cycles with gravimetric assessment of wear atevery 0.5 million cycles. Undiluted bovine serum was used as lubricantwith 0.3 wt % sodium azide as antibacterial agent and 1 mM EDTA aschelating agent. The wear rate was determined by linear regression ofthe weight change of each pin over number of cycles from 0.5 to 2million cycles.

The pin-on-disc (POD) wear rates of 0.1 and 0.3 wt % blended andirradiated UHMWPE were both higher than the wear rates that werepublished for 100-kGy irradiated and melted UHMWPE (see Muratoglu etal., Effect of Radiation, Heat, and Aging on In Vitro Wear Resistance ofPolyethylene. Clinical Orthopaedics & Related Research, 2003. 417: p.253-262). The in vitro wear rates obtained from POD testing for 0.1 and0.3 wt %/α-tocopherol-blended, and 100-kGy irradiated UHMWPE followingaccelerated aging were 2.10±0.17 and 5.01±0.76 mg/million cycle (MC),respectively. The wear rate for the 0.3 wt % blended UHMWPE was higherthan that for 0.1 wt % blended UHMWPE (p=0.018).

Example 7 Mechanical Properties of Blended and Irradiated UHMWPE as aFunction of Vitamin E Concentration and Radiation Dose

GUR 1050 powder was blended with α-tocopherol and consolidated.Consolidated GUR 1050 UHMWPE powder (consolidated without α-tocopherol)was used as virgin (control) material. The concentrations at whichα-tocopherol was incorporated in the UHMWPE were 0.02, 0.05, 0.1, 0.3and 1.0 wt/wt %. The blends were first prepared in 5 wt % forconsistency, after which they were diluted down to their respectiveconcentrations by adding UHMWPE powder. The molded blocks containing0.1, 0.3 and 1.0 wt % were packaged under vacuum and γ-irradiated to 25,65, 100, 150 and 200 kGy.

Dog-bone shaped specimens (n=5 each) were stamped from virgin, 0.1 and0.3 wt % α-tocopherol-blended and irradiated UHMWPE in accordance withASTM D638, standard test method for tensile properties of plastics.These samples were then tested in accordance with ASTM D-638 using a MTSII machine (Eden Prairie, Minn.) at a crosshead speed of 10 min/min.

The mechanical strength of virgin UHMWPE (indicators are ultimatetensile strength (UTS), elongation at break (EAB) and work to failure(WF)) decreased with increasing radiation dose (FIGS. 9A, 9B, and 9C).In contrast, these indicators stayed the same or increased withincreasing radiation dose until about 100 kGy irradiation for vitaminE-blended and irradiated UHMWPEs. These results suggested that thepresence of vitamin E during irradiation not only decreasedcross-linking but also increased the scissioning of polyethylene chains.This resulted in higher elongation-to-break than the virgin UHMWPEs.

These results further suggested that the mechanical properties of UHMWPEcan be manipulated by the presence and concentration of vitamin E inUHMWPE during the irradiation as well as the radiation dose.

Example 8 Gradient Cross-Linking by Irradiating Vitamin E-DopedConventional UHMWPE

Cylinders (3 cm diameter, 3.75 cm length) were machined from slabcompression molded GUR1050 UHMWPE.

A bath of vitamin E (D,L-α-tocopherol) was heated to 170° C. Onecylinder of UHMWPE was placed in the vitamin E bath and kept for 15minutes. During this time, the surface of the cylinder (about 2-3 mm)became transparent, showing melting at the surface. In this way, thesurface of the UHMWPE block was doped with vitamin E in the melt phase,enhancing the diffusion rate above that which would occur at below themelting point (approximately 137° C.).

The block was packaged in vacuum after doping and irradiated by gammairradiation to 100 kGy.

Fourier Transform Infrared Spectroscopy (FTIR) was performed on thinsections (approximately 150 μm) cut using a sledge microtome. Infraredspectra were collected from one edge of the sample to the other in 100μm and 500 μm intervals, with each spectrum recorded as an average of 32individual scans. The infrared spectra were analyzed to calculate avitamin E index as the ratio of the areas under the α-tocopherolabsorbance at 1262 cm⁻¹ (12454275 cm⁻¹) and the polyethylene skeletalabsorbance at 1895 cm⁻¹ (1850-1985 cm⁻¹). The vitamin E index wasplotted as a function of distance away from the surface to present thevitamin E concentration profiles of the doped samples.

Likewise, a transvinylene index (TVI) was calculated as the ratio of theareas under the transvinylene absorbance at 965 cm⁻¹ and thepolyethylene skeletal absorbance at 1895 cm⁻¹ (1850-1985 cm⁻¹). TVI hasbeen shown to increase with increasing radiation dose and is about0.12-0.15 for a virgin, 100-kGy irradiated UHMWPE.

The vitamin E concentration profile of the block before irradiation andthe transvinylene groups after irradiation are shown as a function ofdepth from the surface in FIG. 10.

Vitamin E inhibited cross-linking in doped UHMWPE, as shown by thedecrease in TVI in the vitamin E-rich surface region of the doped, thenirradiated UHMPE block. Vitamin E penetration, defined as an index levelof 0.02 was until about 2 mm into the sample and the TVI reached thoseobserved for a virgin UHMWPE at about 2-3.0 mm.

These results show that the cross-link density of a UHMWPE can bemanipulated by the presence of diffused vitamin E.

Similarly, one cylinder was doped in a vitamin E bath at 132° C. belowthe melting point of UHMWPE for 4 hours and subsequently irradiated bygamma irradiation to 100 kGy.

Example 9 Mechanical Properties of Doped UHMWPE with Subsequent ColdIrradiation, and Cold Irradiation and Melting

Consolidated GUR 1050 (3″ diameter) was machined into thin sections (3.2mm thickness). These samples were then doped with vitamin E(D,L-α-tocopherol) in 0.5 atm partial nitrogen/vacuum at 132° C.Following doping, they were taken out of vitamin E, wiped clean withethanol to remove excess, and placed in 0.5 atm partial nitrogen/vacuumat 132° C. for homogenization. Doping and homogenization conditions ofthe four study groups are shown in Table 3 as well as the averagevitamin E index levels along the sample depth. The vitamin E index wasdetermined by using FTIR to spectroscopy as described in Example 8.

TABLE 3 Processing parameters and amount of α-tocopherol in samplesI-IV. Doping Doping Homogenization Average Sample Temperature DurationTemperature Homogenization vitamin E ID (° C.) (h) (° C.) Duration (h)index I 132 5 132 48 0.92 ± 0.10 II 132 24 132 48 1.98 ± 0.07 III 132 48132 72 3.80 ± 0.13 IV 132 96 132 96 4.62 ± 0.12

Subsequent to doping and homogenization, thin sections were processed inthe following manner.

1. No irradiation.

2. Cold e-beam irradiation to 100 kGy in air.

3. Cold e-beam irradiation to 100 kGy in air with subsequent melting at155° C.

Two other controls used in this study were previously tested 100 kGyγ-irradiated in N₂ GUR 1050 (CI) and 100 kGy e-beam irradiated in N₂ GUR1050 (CISM). Electron beam irradiation was performed at the High VoltageLaboratories at Massachusetts Institute of Technology (Cambridge, Mass.)using a 2.5 MeV Van de Graff generator.

For the doped/homogenized and irradiated samples, it was establishedthat the profiles of α-tocopherol after irradiation were uniform byusing FTIR spectroscopy.

Dog-bone shaped samples (n=5) were stamped out of the thin sections inaccordance with ASTM D-638 Standard method for tensile properties ofplastics. These tensile specimens were tested on a MTS II Machine (EdenPrune, Minn.) at a crosshead speed of 10 mm/min until failure.

Some important mechanical properties of study materials are shown inTable 4.

TABLE 4 Mechanical properties of α-tocopherol doped test samples andcontrols. Vitamin E index before Engineering Strain Sample irradiationUTS* (MPa) at Break (%) YS (MPa) Unirradiated GUR 1050 — 54 ± 7  970 ±66 23 ± 3 100 kGy irradiated (CI) 100 kGy — 45 ± 1 NA 24 ± 1 Vitamin Edoped/not irradiated I 0.92 ± 0.10 59 ± 2 1107 ± 36 21.8 ± 0.4 II 1.98 ±0.07 56 ± 2 1046 ± 43 21.2 ± 0.8 III 3.80 ± 0.13 54 ± 1  988 ± 24 20 ± 0IV 4.62 ± 0.12 53 ± 1  953 ± 22 19 ± 0 Vitamin E doped/100 kGyirradiated I 0.92 ± 0.10 53 ± 3 1072 ± 60 23 ± 0 II 1.98 ± 0.07 53 ± 41081 ± 87   22 ± 0.7 III 3.80 ± 0.13 48 ± 3 1013 ± 78 20.8 ± 0.4 IV 4.62± 0.12 48 ± 2 1058 ± 66 19.6 ± 0.5 Vitamin E doped/100 kGyirradiated/melted I 0.92 ± 0.10 59 ± 2 1505 ± 87 21 ± 0 II 1.98 ± 0.0754 ± 4  1493 ± 136 19.6 ± 0.5 III 3.80 ± 0.13 50 ± 3 1397 ± 94 18.8 ±0.4 IV 4.62 ± 0.12 50 ± 5  1440 ± 162 18.8 ± 0.4 *UTS: Ultimate tensilestrength, EAB: Elongation at break, YS: Yield strength.

The effect of irradiation alone was observed by comparing unirradiatedand 100 kGy irradiated UHMWPE. While the yield strength remains similar,all mechanical properties were decreased as a result of irradiation tothis high dose level. Doped/not irradiated UHMWPE was compared tounirradiated UHMWPE to observe the effect of vitamin E on unirradiatedUHMWPE. The engineering strain at break, which is an indicator ofplasticity was similar to that of unirradiated GUR 1050 (p>0.05).

All mechanical properties of doped/irradiated UHMWPE have higher valuesthan that for irradiated material. The engineering strain is especiallysignificant showing that doped/irradiated UHMWPE shows higher plasticitythan irradiated UHMWPE.

The engineering strain for doped/irradiated/melted UHMWPE wassignificantly higher than that for irradiated/melted samples (p<0.0001).

Example 10 Mechanical Properties of Vitamin E-Containing UHMWPE withSubsequent Melt-Irradiation

Consolidated GUR 1050 (3″ diameter) was machined into thin sections (3.2mm thickness). These samples were then doped with vitamin E(D,L-α-tocopherol) in 0.5 atm partial nitrogen/vacuum at 132° C.Following doping, they were taken out of vitamin E, wiped clean withethanol to remove excess, and placed in 0.5 atm partial nitrogen/vacuumat 132° C. for homogenization. Doping and homogenization conditions ofthe four study groups are shown in Table 3 as well as the averagevitamin E index levels along the sample depth. The vitamin E index wasdetermined by using FTIR spectroscopy as described in Example 8.

Then these samples were irradiated to 100-kGy by electron beamirradiation under flowing nitrogen (12.5 kGy/pass, HVRL, MIT, Cambridge,Mass.) at 180° C.

The mechanical properties of vitamin E-doped and melt irradiated UHMWPEare shown in Table 5. The elongation-at-break of doped andmelt-irradiated UHMWPE was similar to that of virgin UHMWPE.

TABLE 5 Mechanical properties of vitamin E doped and melt-irradiatedtest samples and controls. EAB is the true elongation at break. VitaminE index Sample before irradiation UTS* (MPa) EAB (%) YS (MPa)Unirradiated GUR 1050 — 54 ± 7 481 23 ± 3 100 kGy irradiated (CI) 100kGy — 45 ± 1 24 ± 1 Vitamin E doped/100 kGy melt-irradiated I 0.92 ±0.10 40 ± 1 481 ± 7  20 ± 1 II 1.98 ± 0.07 42 ± 1 506 ± 16 20 ± 1 III3.80 ± 0.13 40 ± 2 515 ± 24 18 ± 0 IV 4.62 ± 0.12 42 ± 4 507 ± 17 18 ± 0

Example 11 Mechanical Properties of Melt-Doped and Irradiated UHMWPE

Consolidated GUR 1050 (3″ diameter) was machined into thin sections (3.2mm thickness). These samples were then doped with vitamin E(D,L-α-tocopherol) in 0.5 atm partial nitrogen/vacuum at 170° C. for 22hours. Following doping, they were taken out of vitamin E, wiped cleanwith ethanol to remove excess, and placed in 0.5 atm partialnitrogen/vacuum at 132° C. for homogenization for 48 hours.

TABLE 6 Mechanical properties of α-tocopherol doped test samples andcontrols. α-tocopherol UTS* Engineering Strain Yield Strength Sampleindex (MPa) at Break (%) (MPa) Unirradiated GUR 1050 — 54 ± 7 970 ± 6623 ± 3 100 kGy irradiated (CI) 100 kGy — 45 ± 1 24 ± 1 α-tocopheroldoped/not irradiated V 12.7 ± 1.4 27 ± 7 1116 ± 88  10 ± 2 α-tocopheroldoped/100 kGy irradiated V 12.7 ± 1.4 27 ± 2 1174 ± 73   9 ± 1α-tocopherol doped/100 kGy irradiated/melted V 12.7 ± 1.4 24 ± 4 1406 ±219  9 ± 1 α-tocopherol doped/100 kGy melt irradiated V 12.7 ± 1.4 28 ±3 1355 ± 256 12 ± 1

One such melt-doped and homogenized thin section was cold irradiated to100 kGy by electron beam irradiation (2.5 MeV beam, 12.5 kGy/pass, HVRL,MIT, Cambridge, Mass.). One was cold irradiated to 100 kGy, then melted.And finally, one was irradiated to 100 kGy at 170° C.

The ultimate tensile strength of all melt-doped and processed UHMWPEwere much lower than that of virgin and virgin irradiated UHMWPE (seeTable 6). The results as shown in Table 6 suggest that melt-dopingUHMWPE resulted in a UHMWPE with low strength and high plasticity.Further melting after irradiation increased the elongation further.

Example 12 Mechanical Properties of Cross-Linked, Vitamin E Diffused andIrradiated UHMWPE (2005)

Electron-beam irradiated UHMWPE (100-kGy; Unmelted Longevity) wasmachined into 3.2 mm-thick sections. These sections were doped withvitamin E at 120° C. for 20 minutes under argon and subsequentlyhomogenized for 24 hours in argon. The resulting vitamin E profile wasdetermined using Fourier Transform Infrared Spectroscopy. These thinsections were then irradiated to 65 and 100 kGy by electron beamirradiation (2.5 MeV Van-de-Graff generator (HVRL, MassachusettsInstitute of Technology, Cambridge, Mass.) at a dose rate of 12.5kGy/pass) or 100 and 200 kGy by gamma irradiation (Steris Isomedix,Northborough, Mass.). Dog-bone shaped tensile specimens (Type V) werestamped out of these thin sections and they were tested per ASTM D638.

The average vitamin E index of 65-kGy irradiated, vitamin E-doped UHMWPEwas 0.13. There were no appreciable changes in the mechanical propertiesof 100-kGy irradiated, vitamin E-doped UHMWPE with subsequent high doseirradiation (Table 7).

Example 13 Gradient Vitamin E Profile by Diffusion

Slab compression molded GUR1050 UHMWPE was packaged in aluminum foilpackaging in vacuum and irradiated to 65 kGy using ⁶⁰Co gammairradiation (Steris Esomedix, Northbrough, Mass.). Unirradiated UHMWPEwas used without irradiation.

Cubes of unirradiated, and 65 kGy irradiated UHMWPE (2 cm) were machinedfrom the stock. Three cubes each were doped in vitamin E by soaking inthe bath at 120° C., 2, 8 and 24 hours.

Both surface concentration and penetration depth increased withincreasing doping time. The overall weight gain due to vitamin E alsoincreased as a function of doping time. The vitamin E concentrationprofiles are shown in FIGS. 11A and 11B. The vitamin E concentrationshowed a gradient from a vitamin E-rich surface to a vitamin E-poorbulk.

TABLE 7 Mechanical properties of cross-linked, vitamin E-diffused andhigh dose irradiated UHMWPEs. UTS UTS Sample range (MPa) (MPa) YS (MPa)WF (kJ/m²) 65 kGy 49 ± 3 22 ± 0 1663 ± 191 65 kGy + Vitamin E 39 ± 3 24± 1 1414 ± 178 65 kGy + Vitamin 42 ± 4 23 ± 1 1516 ± 304 E + 65 kGye-beam 65 kGy + Vitamin 42 ± 4 23 ± 2 1563 ± 226 E + 100 kGy e-beam 100kGy 46 ± 4 21 ± 1 1397 ± 211 100 kGy + Vitamin E 33-45 40 ± 6 21 ± 21285 ± 287 100 kGy + Vitamin 36-52 44 ± 7 22 ± 1 1318 ± 355 E + 100 kGye-beam 100 kGy + Vitamin 28-50 42 ± 9 24 ± 1 1242 ± 411 E + 100 kGygamma 100 kGy + Vitamin 35-46 40 ± 9 25 ± 0 1131 ± 191 E + 200 kGy gamma

Example 14 Gradient and Uniform Vitamin E Profile by Doping andHomogenization

GUR1050 UHMWPE bar stock (thickness 4 cm) was irradiated to 100-kGy bye-beam irradiation (Iotron Inc., Vancouver, BC) under vacuum in foilpackaging. Approximately 45×90×25 mm blocks were machined out of thisirradiated stock. Two blocks was doped in vitamin E at 120° C. for 6hours. Excess vitamin E was wiped from the surfaces. Subsequently, onewas homogenized in argon for 50 hrs at 130° C. and the other washomogenized in argon for 216 hrs at 130° C.

The vitamin E concentration profiles for these two doped and homogenizedUHMWPEs are shown in FIG. 12. Homogenizing for 50 hrs resulted in agradient vitamin E profile and homogenization for 216 hours resulted ina uniform profile.

Example 15 The Cross-Linking Density of Blended/Virgin CompressionMolded and Irradiated Puck

Two puck-shaped pieces of UHMWPE, both 2.5″ in diameter, were directcompression molded (DCM). One puck was 1″ thick, the other one was 1.5″thick. The 1″ thick puck was produced using a standard molding cycle inwhich the bottom half of the mold was filled with GUR 1050 powdercontaining 0.5 wt % α-tocopherol and the top half with virgin GUR 1050powder. The 1.5″ thick puck was produced using a modified molding cycle,in which the bottom half of the mold was filled with GUR 1050 powdercontaining 0.5 wt % α-tocopherol and compressed at room temperatureunder a pressure of 1220 psi. Following release of the pressure, the tophalf of the mold was filled with virgin GUR 1050 powder followed by astandard DCM cycle. The pucks were subjected to 100-kGy e-beamirradiation at 5 kGy/pass at about room temperature.

A 3 mm-thick sample (approximately 3 mm by 3 mm in crossection) was cutfrom the virgin UHMWPE surface and a similar sample was cut from thecore of the blended UHMWPE bulk after irradiation. These samples weretested on a swell ratio tester by injecting xylene at 130° C. into achamber where the sample height is recorded prior to injection andcontinuously while the sample swells in hot xylene. The cross-linkdensity of the irradiated samples was calculated as described previously(see Muratoglu et al., Unified Wear Model for Highly CrosslinkedUltra-high Molecular Weight Polyethylenes (UHMWPE). Biomaterials, 1999.20(16): p. 1463-1470) and are reported as mol/m³.

The cross-link density of the highly cross-linked virgin UHMWPE takenfrom the surface was 271 mol/m³ and the low cross-linked blended UHMWPEtaken from the bulk was 84 mol/m³.

Example 16 Elimination of Free Radicals in Irradiated UHMWPE by HighPressure Crystallization or High Pressure Annealing

Six blocks (approximately 1.5 by 1.5 in, 2 in thickness) of GUR1050UHMWPE were machined from 65- and 100-kGy irradiated stock. One block ofeach stock were separately high pressure annealed by pressurizing in ahigh pressure chamber to 55, 000 psi and heating to 200° C. and 220° C.to transition into the hexagonal phase from the solid orthorhombicphase. They were also separately high pressure crystallized by heatingfirst to 200° C., then pressurizing to 55,000 psi to transition into thehexagonal phase from the melt phase. Two blocks without high pressurecrystallization or annealing were used as controls.

Small samples (approximately 3 by 3 mm in cross-section, 2 cm in length)were tested for electron spin resonance measurements to determine theamount of free radicals in the samples.

The free radical concentration of all samples are shown in Table 8. Bothhigh pressure crystallization through the melt-phase (Route I) and highpressure crystallization through the solid-phase (Route 11) eliminatedmost of the free radicals in irradiated UHMWPE (see Table 8, also seeFIG. 13).

TABLE 8 The free radical concentrations of irradiated and irradiated andhigh pressure crystallized UHMWPE. Free radical Sample concentration(spins/g) (×10¹⁴⁾ 65-kGy control 30.8 65-kGy Route I 55 ksi/200° C. 1.4265-kGy Route II 55 ksi/200° C. 0.76 65-kGy Route II 55 ksi/220° C. 1.05100-kGy control 113 100-kGy Route I 55 ksi/200° C. N/A 100-kGy Route II55 ksi/200° C. 3.82 100-kGy Route II 55 ksi/220° C. 2.82

Example 17 Melting Subsequent to Blending with Vitamin E and Irradiation

Vitamin E is blended with UHMWPE powder at a concentration of 0.01,0.02, 0.05, 0.1, 0.2, 0.5, 1.0, 2.5 or 50 wt %. The blend is thenconsolidated into Vitamin E-blended blocks (for example, 5 cm by 10 cmby 12 cm) by compression molding. Some blocks are subsequentlyirradiated to 25, 50, 75, 100, 125, 150, 200 and 250 kGy using gamma ore-beam irradiation.

Some blocks are heated to above the melting temperature of blendedUHMWPE (approximately 137° C. at ambient pressure) and held. The holdingtime can be 10 minutes to several days. Depending on the amount of timeat temperature and the size of the block, some parts or all parts of theblock are molten.

Melting of irradiated, vitamin E-containing UHMWPE can change thedistribution of vitamin E concentration and also can change themechanical properties of UHMWPE. These changes can be induced by changesin crystallinity and/or by the plasticization effect of vitamin E atcertain concentrations. Melting during or after irradiation also reducesthe residual free radicals in polyethylene to undetectable levels.

Example 18 Vitamin E Concentration Profile of Diffused RadiationCross-Linked UHMWPE

Blocks (10 mm thick) were machined from 100-kGy irradiated UHMWPE(GUR1050, Orthoplastics, Lancashire, UK). One block each was doped inpure vitamin E at 100, 105, 110, and 120° C. for 24 hours. One blockeach was doped in pure vitamin E at 105° C. for 24, 48, and 72 hours.

The vitamin E concentration profiles were calculated as describedpreviously (Oral et al. Characterization of irradiated blends ofα-tocopherol and UHMWPE, Biomaterials, 26: 6657-6663 (2005)) by FourierTransform Infrared Spectroscopy (FTIR). Briefly, the area under theα-tocopherol peak at 1265 cm⁻¹ (limits 1245-1275 cm⁻¹) was normalized tothe polyethylene peak at 1895 cm⁻¹ as a vitamin E index (A. U.). Then,this α-tocopherol or vitamin E index (A.U.) was reported as a functionof depth away from the free surface (exterior regions) into the bulk(interior regions) of the sample. The penetration depth was defined asthe depth at which the vitamin E index was below 0.02.

Both surface vitamin E concentration and vitamin E penetration depth wasincreased as temperature increased (FIG. 15A). At the same dopingtemperature, increasing time increased depth of penetration (FIG. 15B).

Example 19 Vitamin E Concentration Profile of Diffused and HomogenizedUHMWPE

Blocks (10 mm thick) were machined from 85-kGy irradiated UHMWPE(GUR1050, Orthoplastics, Lancashire, UK). One block was doped in purevitamin E at 120° C. for 4 hours. Another block was doped in purevitamin E at 120° C. for 4 hours followed by 24 hours of homogenizationin argon.

Vitamin E concentration profiles were determined as described in Example18.

Homogenization subsequent to doping in vitamin E enhanced thepenetration depth and decreased the surface concentration due todiffusion of the vitamin E at the surface into the bulk of the sample(FIG. 16).

Example 20 Vitamin E Concentration Profiles of Vitamin E-Blended UHMWPEand Subsequently Irradiated Samples

Vitamin E (D,L-α-tocopherol, Alfa Aesar, Ward Hill, Mass.) was mixedwith GUR1050 UHMWPE powder at a concentration of 5 wt/wt %, then dilutedfor consistency with UHMWPE resin powder to 1.0 wt %. The mixture wasconsolidated into α-tocopherol-blended blocks (5.5 cm×10 cm×12 cm) bycompression molding.

One block was subsequently irradiated to 100-kGy using gamma irradiation(Steris Isomedix, Northborough, Mass.). The vitamin E concentrationprofiles of 5 cm-thick unirradiated and irradiated pieces weredetermined using FTIR spectroscopy as described in Example 18 and areshown in FIG. 17.

Some vitamin E was used during high dose irradiation (100 kGy) asdetermined by the decrease in the vitamin E absorbance and concentrationafter irradiation.

Example 21 Extraction of Vitamin E Concentration Profiles of VitaminE-Blended UHMWPE Samples

Vitamin E (D,L-α-tocopherol, Alfa Aesar, Ward Hill, Mass.) was mixedwith GUR1050 UHMWPE powder at a concentration of 5 wt/wt %, then dilutedfor consistency with UHMWPE resin powder to 1.0 wt %. The mixture wasconsolidated into α-tocopherol-blended blocks (5.5 cm×10 cm×12 cm) bycompression molding.

One block was subsequently irradiated to 100-kGy using gamma irradiation(Steris Isomedix, Northborough, Mass.).

The surface vitamin E concentration was reduced using extraction inboiling ethanol for 16 hours in both samples. The vitamin Econcentration profiles of unirradiated and irradiated UHMWPE before andafter extraction were determined using FTIR spectroscopy as described inExample 18 and are shown in FIG. 18.

Boiling ethanol was instrumental in reducing the surface concentrationof vitamin E in both unirradiated and irradiated 1 wt %α-tocopherol-blended consolidated UHMWPE blocks (FIG. 18).

Example 22 Solubilization of Vitamin E in an Aqueous Solution orEmulsion

Surfactant Tween 80 (Polyethylene glycol sorbitan monooleate, Sigma, St.Louis, Mo.) and vitamin E (D, L-α-tocopherol, DSM Nutritional Products,Pouhkeepsie, N.J.) were heated at 60° C. A 20 mg of vitamin E wasweighed in an Erlenmeyer flask, then Tween 80 was added to the vitamin Ein the desired amount so that amount of Tween 80 was 3 weight percentageof the solution. A 20 mL of water was added to this mixture. The mixturewas boiled under reflux until a clear solution or a stable emulsion wasobtained. This emulsified solution contained 1 mg/mL vitamin E (solutioncontaining 3 wt % Tween 80 in deionized water) and was clear.Alternatively, the same amount of vitamin E was mixed with 0.25 wt %Tween 80 in a 20 mL 1 wt % ethanol/water emulsion was cloudy.

A 5 mg/mL vitamin E solution was prepared by using 10-15 wt % Tween 80in deionized water and a 5 mg/mL vitamin E emulsion was prepared byusing 0.25 wt % Tween 80 in a 20 mL 6 wt % ethanol/water emulsion.

Example 23 Vitamin E Detection Limits

Vitamin E (D,Lα-tocopherol, Alfa Aesar, Ward Hill, Mass.) was mixed withGUR1050 UHMWPE powder at a concentration of 5 wt/wt %, then diluted forconsistency with UHMWPE resin powder to 0.1 and 1.0 wt %. The mixtureswere consolidated into α-tocopherol-blended blocks (5.5 cm×10 cm×12 cm)by compression molding.

The vitamin E concentration profiles were determined using FTIRspectroscopy as described in Example 18 and are shown in FIG. 19 incomparison with a control UHMWPE containing no vitamin E. The detectionlimit by the spectroscopic technique was set at 0.01 based on theseresults.

Example 24 Extraction of Vitamin E from the Surface of Diffused andHomogenized UHMWPE Subsequent to Irradiation Using an Emulsion with aSurfactant

Blocks (20 mm cubes) of 100-kGy irradiated UHMWPE were doped withvitamin E at 120° C. for 2 hours under argon purge. At the end of thedoping period, the samples were taken out of the vitamin E and cooleddown to room temperature. The excess vitamin E was wiped off usingcotton gauze. The samples were then homogenized under argon purge at120° C. for 24 hours. At the end of the homogenization period, thesamples were cooled down to room temperature under argon purge.

A 10 wt % Tween 80 solution was prepared in deionized water. A pressurechamber was heated to 120° C. in an air convection oven. The solutionwas placed in the heated chamber with the UHMWPE samples and the chamberwas sealed. The extraction of vitamin E from the doped and homogenizedUHMWPE continued for 20 hours under self generated pressure. At the endof the 20 hours, the chamber was cooled down to room temperature and thepressure was released.

Alternatively, a 20 wt % Tween 80 solution and a 10 wt % Tween 80emulsion in 10 wt % ethanol was prepared in deionized water. Thesolution was placed in an Erlenmeyer flask with the UHMWPE samples andwas boiled under reflux at ambient pressure for 20 hours.

The vitamin E concentration profiles of doped and homogenized UHMWPE andextracted UHMWPE were determined as described in Example 18. The surfaceconcentration of extracted samples was significantly reduced both underself-generated pressure at 120° C. and at ambient pressure at boilingtemperature (FIGS. 20 and 21, respectively).

Example 25 Hexane Extraction of Diffused, Homogenized and SterilizedUHMWPE

Two different acetabular liners: an 85-kGy irradiated,α-tocopherol-doped, and gamma-sterilized UHMWPE and an 85-kGy irradiatedUHMWPE were tested. Both liners were prepared with a 5-mm nominalthickness. Both liners had an inner diameter of 36-mm.

The two liners were machined from GUR1050 UHMWPE. Both liners werepackaged under argon gas. The package was then gamma-irradiated to85-kGy. One of the liners was used as irradiated control. The otherliner was subsequently doped in α-tocopherol at 120° C. for 2 hours andhomogenized at 120° C. for 24 hours under argon gas. The doped andannealed liner was packaged in argon gas and gamma sterilized.

Each liner was cut into four quarters. One was analyzed as control. Onewas extracted in boiling hexane (65-70° C.) in separate reflux chambersfor 72 hours. One was hexane extracted and accelerated bomb aged at 70°C. for 2 weeks at 5 atm. of O₂. One was hexane extracted and acceleratedoven aged at 80° C. for 6 weeks in air.

Hexane extraction for 72 hours resulted in the migration of detectableα-tocopherol out of the acetabular liner pieces (FIG. 22). Although85-kGy irradiated UHMWPE showed high oxidation after accelerated agingboth on the surface (FIG. 23) and bulk (FIG. 24), hexane extractedvitamin E-doped samples were still stable against oxidation, exhibitingonly baseline levels of oxidation after 2 weeks of accelerated aging inoxygen at 5 atm and 70° C. (ASTM F2003-02). The oxidation observed injust irradiated samples was not due to hexane extraction.

Example 26 The Effect of Sterilization on the α-Tocopherol ConcentrationProfile

GUR1050 UHMWPE was annealed at 130° C. for 5 hours, 124° C. for 5 hours,119° C. for 5 hours, 113° C. for 5 hours and 105° C. for 5 hours, thencooled to room temperature over 10 hours. A 4 cm-thick pieces ofannealed UHMWPE were irradiated to 100-kGy at 25 kGy/pass using a 10 MeVelectron generator (Iotron Inc., Vancouver, BC) in vacuum. Hemisphericalperforms (approximately 6.8 mm thick) for acetabular liners were dopedfor 2.5 hours at 120° C. under argon purge, followed by 40 hours ofhomogenization at 120° C. as described in Example 19. Canine acetabularliners (approximately 2.6 mm thick) were machined from these preforms.Then, the liners were individually packaged in vacuum and sterilized bygamma irradiation.

The vitamin E concentration profiles of doped and homogenized preforms,machined acetabular liners, and sterilized acetabular liners weredetermined as described in Example 18 and are shown in FIG. 25.

These profiles show that the surface and bulk concentrations can becontrolled by machining after doping and homogenization. They alsoshowed that sterilization dose radiation (25-40 kGy) did not have anobservable difference in the vitamin E profile at this vitamin Econcentration.

Alternatively, canine acetabular liners were directly machined from100-kGy irradiated annealed UHMWPE. These liners were doped with vitaminE and homogenized as described above. One set of these liners weresubjected to extraction in 15 wt % Tween 80 solution in a 5 wt %ethanol/water emulsion at 120° C. under self-generated pressure asdescribed in Example 24,

The vitamin E concentration profiles of doped and homogenized acetabularliners before and after extraction were determined as described inExample 18 and are shown in FIG. 26.

Example 27 The Potency of α-Tocopherol Against High Dose Irradiation

A 3 cm cube of 100-kGy irradiated GUR1050 UHMWPE was doped with vitaminE for 48 hours at 100° C. This cube was accelerated aged at 70° C. in 5atm O₂ for 2 weeks. To determine the α-tocopherol or oxidation profileinto polyethylene, the samples were cut in half and sectioned (150 μm)using an LKB Sledge Microtome (Sweden). The thin sections were thenanalyzed using a BioRad UMA 500 infrared microscope (Natick, Mass.).Infrared spectra were collected with an aperture size of 50×50 μm as afunction of depth away from the free surface of the cube. The infraredspectra were analyzed to calculate a “sensitive α-tocopherol index”, asthe ratio of the areas under the 1265 cm⁻¹ α-tocopherol and 1895 cm⁻¹polyethylene skeletal absorbances. An oxidation index was calculated asthe ratio of the areas under the 1740 cm⁻¹ carbonyl and 1370 cm⁻¹methylene stretching absorbances.

The depth at which there was significant oxidation was where the vitaminE index dropped below 0.01 (FIG. 27). Hence, the bulk of the samplecontaining less than this amount was susceptible to oxidation.Therefore, it was desirable to have a vitamin E index of at least 0.01throughout the entire sample.

Also, the effect of high dose irradiation on blended samples is shown inFIG. 28. The oxidation levels after irradiation increased withdecreasing vitamin E concentration in the blends.

Example 28 Vitamin E Concentration Profiles of Real-Time Aged Doped,Homogenized and Sterilized UHMWPE

Hot isostatically pressed GUR1050 UHMWPE stock (Biomet, Inc.) was usedin all experiments. Blocks (30×30×10 mm) were machined and γ-irradiatedto 85-kGy in inert gas. The blocks were doped with α-tocopherol (VitaminE) at 120° C. for 5 hours followed by homogenization at 120° C. in argonfor 64 hours. All samples were packaged in inert gas and γ-sterilized.

Blocks were aged on the shelf at room temperature, at 40° C. in air andat 40° C. in water for 16 months. Three sections each were cut at 1, 2,4, 7, 12, and 16 months to determine the vitamin E concentrationprofiles, which were determined using FTIR spectroscopy as described inExample 18 and are shown in FIGS. 29, 30 and 31.

Although the surface vitamin E concentration of shelf-aged samples didnot decrease significantly, the surface vitamin E concentration ofsamples aged in air and water at 40° C. decreased considerably (FIGS.29, 30, and 31, respectively). The higher extraction of vitamin E fromthe surface in the samples aged in water was due to the decrease in thesolubility of the UHMWPE at 40° C. compared to 120° C., where it wasdoped and homogenized and the aqueous environment carrying the extractedvitamin E away from the surface, increasing the driving force.

This Example shows that when stored in air or in water at 40° C., theirradiated and α-tocopherol-doped UHMWPE loses about 10% of theα-tocopherol over about the first six months. The presence of excessα-tocopherol in the joint space may possibly lead to an adversebiological response. Therefore, in order to avoid such complication, itis necessary to extract α-tocopherol from the polymeric material priorto placement and/or implantation into the body. Decreasing theconcentration decreases the driving force of the α-tocopherol out of theimplant, minimizing father elution.

Example 29 Melting Subsequent to Blending with Vitamin E, Extraction andIrradiation

Vitamin E is blended with UHMWPE powder at a concentration of 0.01,0.02, 0.05, 0.1, 0.2, 0.5, 1.0, 2.5 or 50 wt %. The blend is thenconsolidated into Vitamin E-blended blocks (for example, 5 cm by 10 cmby 12 cm) by compression molding.

A Tween 80 solution is prepared in deionized water. A pressure chamberis heated to 100, 110, 120, 130, 140, 150, 160, 170 or 180° C. in an airconvection oven. The solution is placed in the heated chamber with theUHMWPE samples and the chamber was sealed. The extraction of vitamin Efrom this homogenized UHMWPE is done for 5, 20, 50 or 200 hours underself generated pressure. At the end of the 20 hours, the chamber iscooled down to room temperature and the pressure is released.

Alternatively, a Tween 80 emulsion in ethanol is prepared in deionizedwater. The solution is placed in an Erlenmeyer flask with the UHMWPEsamples and is boiled under reflux at ambient pressure.

Alternatively, the samples are boiled in hexane, xylene or ethanol for5, 20, 50 or 200 hours. Then, they are dried in vacuum or partial vacuumat room temperature or at a temperature up to 137° C. for 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days or more.

Some blocks are subsequently irradiated to 25, 50, 75, 100, 125, 150,200 and 250 kGy using gamma or e-beam irradiation.

Some blocks are heated to above the melting temperature of blendedUHMWPE (approximately 137° C. at ambient pressure) and held. The holdingtime can be 10 minutes to several days. Depending on the amount of timeat temperature and the size of the block, some parts or all parts of theblock are molten.

Melting of irradiated, vitamin E-containing UHMWPE can change thedistribution of vitamin E concentration and also can change themechanical properties of UHMWPE. These changes can be induced by changesin crystallinity and/or by the plasticization effect of vitamin E atcertain concentrations.

Example 30 Melting Subsequent to Doping with Vitamin E, HomogenizationExtraction and Irradiation

UHMWPE is blended with vitamin E and homogenized. A Tween 80 solution isprepared in deionized water. A pressure chamber is heated to 100, 110,120, 130, 140, 150, 160, 170 or 180° C. in an air convection oven. Thesolution is placed in the heated chamber with the UHMWPE samples and thechamber was sealed. The extraction of vitamin E from this homogenizedUHMWPE is done for 5, 20, 50 or 200 hours under self generated pressure.At the end of the 20 hours, the chamber is cooled down to roomtemperature and the pressure is released.

Alternatively, a Tween 80 emulsion in ethanol is prepared in deionizedwater. The solution is placed in an Erlenmeyer flask with the UHMWPEsamples and is boiled under reflux at ambient pressure.

Alternatively, the samples are boiled in hexane, xylene or ethanol for5, 20, 50 or 200 hours. Then, they are dried in vacuum or partial vacuumat room temperature or at a temperature up to 137° C. for 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days.

Some blocks are subsequently irradiated to 25, 50, 75, 100, 125, 150,200 and 250 kGy using gamma or e-beam irradiation.

Some irradiated blocks are heated to above the melting temperature ofblended UHMWPE (approximately 137° C. at ambient pressure) and held. Theholding time can be 10 minutes to several days. Depending on the amountof time at temperature and the size of the block, some parts or allparts of the block are molten.

Melting of irradiated, vitamin E-containing UHMWPE can change thedistribution of vitamin E concentration and also can change themechanical properties of UHMWPE. These changes can be induced by changesin crystallinity and/or by the plasticization effect of vitamin E atcertain concentrations.

Example 31 Gradient Cross-Linking by Blending Two Different Vitamin EConcentrations Followed by Irradiation

0.05 wt % vitamin E-containing UHMWPE and 0.5 wt % vitamin E-containingUHMWPE were compression molded to obtain blocks with gradient vitamin Econcentration (FIG. 32). These blocks (50 mm diameter parallel togradient, 38 mm height perpendicular to gradient) were then irradiatedby electron beam irradiation at room temperature to 150 kGy in air at 50kGy/pass.

Vitamin E concentration gradient was determined by using FourierTransform Infrared Spectroscopy (FTIR) as a function of depth away fromthe surface of the low vitamin E concentration side of the blockperpendicular to the gradient. The resulting concentration profiles atthe gradient region before and after irradiation are shown in FIG. 33.Since some vitamin E is used during irradiation, the overall indexvalues were decreased after irradiation.

Thin sections were machined out of gradient irradiated UHMWPEperpendicular to the gradient. Cross-link density measurements ofgradient cross-linked UHMWPE (n=3 each) were performed on small samples(approximately 3×3×3 mm). The samples were weighed before swelling inxylene at 130° C. and they were weighed in xylene immediately afterswelling in xylene. Therefore, the amount of xylene uptake wasdetermined gravimetrically, and then converted to volumetric uptake bydividing by the density of xylene; 0.75 g/cc. By assuming the density ofpolyethylene to be approximately 0.99 g/cc, the volumetric swell ratioof cross-linked UHMWPE was then determined. The cross-link density wascalculated using the swell ratio as described previously (see Muratogluet al., Unified Wear Model for Highly Crosslinked Ultra-high MolecularWeight Polyethylenes (UHMWPE). Biomaterials, 1999. 20(16): p. 1463-1470)and are reported as mol/m³. The cross-link density was determined atthree different spatial locations in the sample; (1) in the low vitaminE side, (2) within the span of the gradient; (3) in the high vitamin Eside.

Cross-link density results are shown in FIG. 34. As expected, highvitamin E-containing side had low cross-link density due to the freeradical scavenging of vitamin E during irradiation, hinderingcross-linking. The low vitamin E containing side was highlycross-linked. The cross-linking level in the gradient region was betweenthat of the low and the high side commensurate with the vitamin Econcentration.

These results showed that spatially controlled cross-linking could beobtained by obtaining a spatially controlled gradient of vitamin Econcentration in UHMWPE prior to irradiation.

Example 32 Interface Strength of Gradient Cross-Linked UHMWPE

The samples containing gradient cross-linking prepared, as described inthe Example 31 above, were machined into 3.2 mm thick sectionsperpendicular to the gradient. From these thin sections, dogbones (TypeV, ASTM D638) and tear test samples (The die according to ASTM D1004 wasused; however the samples were only 3.8 cm long) were stamped.

The ultimate tensile strength (UTS) of the high vitamin E-containingUHMWPE was higher than the rest of the samples due to lower cross-linkdensity after irradiation (FIG. 35). In fact, the UTS of this sample wascomparable to the gradient sample before irradiation showing thatcross-linking was not sufficient to affect the mechanical propertiessignificantly in this sample. In contrast, the UTS of low vitaminE-containing UHMWPE was decreased compared to the gradient sample beforeirradiation and was the lowest due to high cross-link density. The UTSof the gradient samples were slightly higher than low vitaminE-containing, highly cross-linked UHMWPE. Also, all samples failedwithin the highly cross-linked region and not at the gradient (FIG. 36).

The tear strength of the higher vitamin E-containing UHMWPE was higherthan the rest of the samples due to lower cross-link density afterirradiation (FIG. 37). In contrast, the tear strength of low vitaminE-containing UHMWPE was decreased compared to the gradient sample beforeirradiation and was the lowest likely due to high cross-link density.The tear strengths of the gradient samples were higher than low vitaminE-containing, highly cross-linked UHMWPE.

These results showed that the interface strength was at least as high asthe strength of the low vitamin E, highly cross-linked UHMWPE and thatinterface failure did not cause the failure of the sample.

Example 33 Wear Resistance of Gradient Cross-Linked UHMWPE

For wear testing, cylindrical pins (9 mm diameter, 13 mm length) weremachined with their flat wear surfaces at the middle of the gradient, atthe edge of the gradient and 2 mm into the highly cross-linked UHMWPE(FIG. 38).

Wear testing was done on a custom-designed bidirectional pin-on-discwear tester against CoCr discs for 1 million cycles in undiluted bovineserum with penicillin-streptomycin and EDTA. The wear rate of gradientcross-linked samples were 1.59±0.08 and 3.52±0.91 mg/million-cycles(MC), respectively, for samples 1 and 3 (FIG. 38). These results showedthat wear resistance was closely related to cross-link density with theregion with high cross-linking resulting in low wear.

Example 34 Manipulation of the Gradient Span

The span of the gradient was manipulated by using several differenttechniques during molding with the process, as shown in FIG. 39(a), suchas (1) by reducing the temperature of molding on the 0.5 wt % vitamin Econtaining side, and (2) by reducing the molding time in addition toplacing a thin sheet of previously molded 0.05 wt % vitamin E in betweenthe powder specimens to be molded to reduce the diffusion of vitamin Efrom the 0.5 wt % to the 0.05 wt % blended powder.

Another strategy was to mold the blocks separately, then place them inthe molding chamber and fuse them together (3). The resultant gradientvitamin E profiles are shown in FIG. 39(b).

The span of the gradient was determined to be 4.3 mm for standardmolding, 3.0 mm for (1), 3.1 mm for (2) and 3.1 mm for (3). Theseresults show that by using these strategies, the span of the gradientcan be reduced.

Example 35 Gradient Cross-Linking by Irradiating Compression MoldedComponents Made with a Mixture of Virgin UHMWPE Powder and Vitamine-Blended UHMWPE Powder

Four puck-shaped samples (3 in diameter, 0.5 in thickness) made from amixture of virgin GUR 1050 powder and vitamin E-blended GUR 1050 powderwere compression molded in a cylindrical mold at 205° C. The peak loadwas 9000 lb and the mold was cooled under load. The samples and theircompositions are listed in Table 9.

TABLE 9 Compositions of compression-molded vitamin E-UHMWPE pucks.Concentration of Overall Vitamin Wt. of Wt. of Vitamin E E-blendedblended virgin concentration powder (wt %) powder (g) powder (g) (wt %)Blend1 10.0 1.0 49.0 0.2 Blend2 5.0 2.0 48.0 0.2 Ctrl1 0.2 50.0 0.0 0.2Ctrl2 0.0 0.0 50.0 0.0

Two of the samples (Blend1 and Blend2) were made from mixtures of virginGUR 1050 powder and vitamin e-blended GUR 1050 powder. Two controlsamples, one containing no vitamin E and the other prepared from pure0.2 wt % vitamin e-blended powder, were also prepared. All four puckswere irradiated to 100 kGy using gamma irradiation under a vacuum seal.

ASTM D638 (Type V specimens) was used to determine the mechanicalproperties of the irradiated samples. The sample thickness was 3.2 mmand the strain rate was 100 mm/min. A laser extensometer was used torecord the elongation at break. The tensile properties of the samplesare shown in Table 10. The values of the ultimate tensile strength (UTS)were similar for all samples within experimental error. Both Blend1 andBlend2 have similar elongation values to Ctrl1, which contained the sameoverall concentration of vitamin E, but significantly higher elongationvalues than Ctrl2, which contained no vitamin E. From these results itis clear that the mechanical properties of the inhomogeneously blendedsamples Blend1 and Blend2 are equal to or better than the mechanicalproperties of the homogeneous blend Ctrl1.

TABLE 10 Tensile properties of compression-molded pucks. UTS (MPa) +/−Yield (MPa) +/− Elongation (%) +/− Blend1 40.5 1.7 22.9 0.4 260 6 Blend243.5 1.2 23.2 0.2 274 7 Ctrl1 42.0 1.8 22.7 0.2 271 17 Ctrl2 41.9 2.022.5 0.2 211 9

Example 36 Gradient Cross-Linking by Irradiating Compression MoldedComponents Made with a Mixture of Virgin UHMWPE Powder and Vitamine-Blended UHMWPE Pellets

A puck-shaped sample (3 in diameter, 0.5 in thickness) made from amixture of virgin GUR 1050 powder (43.6 g) and vitamin E-blended pellets(11.0 g, pellets contained 5 wt % vitamin E) was compression molded in acylindrical mold at 205° C. The vitamin E-blended pellets were preparedfrom vitamin E-blended powder (5 wt % vitamin E) that was consolidatedinto small discs (1 in diameter, 0.125 in thick). The discs were thenchopped up with a razor-blade into small cubes approximately 4 mm (⅛ in)on a side. These pellets were then mixed by hand with the virgin UHMWPEpowder and consolidated. The peak load was 9000 lb and the mold wascooled under load. The puck had obvious inhomogeneities in vitamin Econcentration which were visible to the naked eye.

The as-molded puck (Blend3) and a control containing no vitamin E (Ctrl)were irradiated to 100 kGy using gamma irradiation under a vacuum seal.After irradiation, both pucks were annealed in argon at 130° C. for 96hours to homogenize the vitamin E concentration in the puck. The samplesand their compositions are listed in Table 11.

The mechanical properties of the Blend3 sample, prepared from a virginpowder/vitamin E-containing UHMWPE pellet mixture, are vastly superiorto the mechanical properties of the control sample, which contains novitamin E. In particular, the yield stress and the elongation both showstatistically significant enhancements.

TABLE 11 Tensile properties of compression-molded pucks. UTS (MPa) +/−Yield (MPa) +/− Elongation (%) +/− Blend3 42.9 6.1 24.4 0.3 308 33 Ctrl41.9 2.0 22.5 0.2 211 9

Example 37 Gradient Preparation by Extracting a Vitamin E Blended UHMWPEby Organic or Aqueous Solvents

One block (approximately 1 cm cube) each of 0.3 and 0.5 wt % vitamin Eblended GUR1050 UHMWPE were boiled in hexane for 1, 2, 4, 6, 24 and 40hours followed by vacuum drying in a vacuum oven at room temperature for7-10 days.

Fourier Transform Infrared Spectroscopy (FTIR) was performed on thinsections (approximately 150 μm) cut using a sledge microtome. Infraredspectra were collected from one edge of the sample to the other in 100μm and 500 μm intervals, with each spectrum recorded as an average of 32individual scans. The infrared spectra were analyzed to calculate avitamin E index as the ratio of the areas under the α-tocopherolabsorbance at 1262 cm⁻¹ (1245-1275 cm⁻¹) and the polyethylene skeletalabsorbance at 1895 cm⁻¹ (1850-1985 cm⁻¹). The vitamin E index wasplotted as a function of distance away from the surface to present thevitamin E concentration profiles of the extracted samples.

The span of the gradient (FIG. 40) was calculated from the surface towhere the vitamin E index did not appreciably change for threeconsecutive data points. The results in Table 12 showed that using thisextraction method, creating vitamin E gradients with spans ranging from0.5 mm to 5 mm was possible.

TABLE 12 Approximate span of the vitamin E gradient from the surface ofblended and hexane extracted UHMWPE. Approximate Extraction timegradient span (mm) (hrs) 0.3 wt % 0.5 wt % 1 0.6 0.5 2 0.6 0.5 4 0.70.8-1.4 6 1.5 1.7 24 7.5 3.0 40 3-4 4.5

Similarly, one block (approximately 1 cm cubes) each of 0.3 and 0.5 wt %vitamin E blended GUR1050 UBMWPE were boiled in a 10% Tween 80(polysorbate 80/polyoxyethylene sorbitan monooleate) solution or a 15%Tween 80/5% ethanol solution for 6 hours followed by vacuum drying in avacuum oven at room temperature for a day.

The extraction by aqueous Tween 80 solution resulted in a narrower spanthan the hexane extracted samples (Tables 12 and 13).

TABLE 13 Approximate span of the vitamin E gradient from the surface ofblended and aqueous Tween 80 solution-extracted UHMWPE. Approximategradient span (mm) Extraction solvent Extraction time (hrs) 0.3 wt % 0.5wt % Tween 80 6 0.7 0.7 Tween 80/ethanol 6 0.8 0.9

The experimental results indicate that by extracting in organic oraqueous solution from the surface of a blended UHMWPE, a gradientconcentration profile of vitamin E can be obtained. These samples canfurther be irradiated to obtain a gradient cross-linked UHMWPE with highcross-linking on the surface and low cross-linking in the bulk.

It is to be understood that the description, specific examples and data,while indicating exemplary embodiments, are given by way of illustrationand are not intended to limit the present invention. Various changes andmodifications within the present invention will become apparent to theskilled artisan from the discussion, disclosure and data containedherein, and thus are considered part of the invention.

What is claimed is: 1-99. (canceled)
 100. An interlocked hybrid materialcomprising an oxidation-resistant cross-linked polymeric material,wherein the method comprising the steps of: a) blending a polymericmaterial with an antioxidant, wherein a first portion of the polymericmaterial is contacted with a concentration of an antioxidant, a secondportion of the polymeric material is contacted with anotherconcentration of the antioxidant, and a third portion of the polymericmaterial is contacted with another concentration of the antioxidant; b)compression molding the antioxidant blended polymeric material toanother piece or a medical implant by layering the third portion of thepolymeric material, the second portion of the polymeric material, andthe first portion of the polymeric material, thereby forming aninterface and an interlocked hybrid material; and c) irradiating theinterlocked hybrid material containing the antioxidant with ionizingradiation, thereby forming an interlocked hybrid material having anoxidation-resistant cross-linked polymeric material.
 101. Theinterlocked hybrid material according to claim 100, wherein the blendedpolymeric material in the first and second portions contain sameconcentrations of the antioxidant.
 102. The interlocked hybrid materialaccording to claim 100, wherein the blended polymeric material in thesecond and third portions contain same concentrations of theantioxidant.
 103. The interlocked hybrid material according to claim100, wherein the blended polymeric material in the first and thirdportions contain different concentrations of the antioxidant.
 104. Theinterlocked hybrid material according to claim 100, wherein the blendedpolymeric material in the first and third portions contain sameconcentrations of the antioxidant.
 105. The interlocked hybrid materialaccording to claim 100, wherein the irradiated interlocked hybridmaterial contains spatially distributed antioxidant and forms aninterlocked hybrid material having an oxidation-resistant cross-linkedpolymeric material having a spatially controlled cross-linking andantioxidant distribution.
 106. The interlocked hybrid material accordingto claim 100, wherein the another piece onto which the resins, flakes orpowders are consolidated is a porous metal.
 107. The interlocked hybridmaterial according to claim 100, wherein the irradiation is performedwhen the interlocked hybrid material is at a temperature above roomtemperature and below the melting point of the polymeric material,wherein the temperature is between about 40° C. and about 135° C. 108.The interlocked hybrid material according to claim 100, wherein theinterlocked hybrid material is a direct compression molded implant. 109.The interlocked hybrid material according to claim 100, wherein theantioxidant is vitamin E.
 110. The interlocked hybrid material accordingto claim 100, wherein the polymeric material is polymeric resin powder,polymeric flakes, polymeric particles, or the like, or a mixturethereof.
 111. The interlocked hybrid material according to claim 100,wherein the antioxidant is vitamin E.
 112. The interlocked hybridmaterial according to claim 100, wherein the irradiated interlockedhybrid material contains spatially distributed antioxidant and forms aninterlocked hybrid material having an oxidation-resistant cross-linkedpolymeric material having a spatially controlled cross-linking andantioxidant distribution.
 113. The interlocked hybrid material accordingto claim 100, wherein the irradiation is carried out at a temperaturethat is above the room temperature and below the melting point of thepolymeric material, wherein the temperature is between about 40° C. andabout 135° C.
 114. The interlocked hybrid material according to claim100, wherein the interlocked hybrid material is a direct compressionmolded hybrid material.
 115. A medical implant comprising theinterlocked hybrid material according to claim 100, wherein theoxidation-resistant interlocked hybrid material is machined, therebyforming oxidation-resistant medical implant.
 116. The medical implantaccording to claim 115, wherein the oxidation-resistant medical implanthaving a spatially controlled crosslinking and antioxidant distributionis packaged and sterilized.